CN1035878C - Indolopyrrolocarbazole derivatives - Google Patents
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- CN1035878C CN1035878C CN93100326A CN93100326A CN1035878C CN 1035878 C CN1035878 C CN 1035878C CN 93100326 A CN93100326 A CN 93100326A CN 93100326 A CN93100326 A CN 93100326A CN 1035878 C CN1035878 C CN 1035878C
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Abstract
A compound represented by the following general formula and a pharmaceutically acceptable salt thereof wherein R1, R2, X1, X2 and G are defined in the specification. This compound has an excellent antitumor effect.
Description
The present invention can be applicable to the medicine and pharmacology field, relates to new indoles and pyrrolo carbazole derivatives, its preparation method and its purposes that can suppress the tumour cell diffusion and show anti-tumor activity.
In the cancer chemotherapy field, a lot of compounds are as antineoplastic agent and by practical application.Yet for various tumours, these compounds are always enough not effective, and tumour cell makes their clinical use complicated (with reference to the 47th Japanese cancer conference paper, 12 to 15 pages (1988)) to the resistance of these medicines.(47th?Japan?Societyof?Cancer?General?Meeting?Article，pages?12?to?15(1988))
Under this situation, in field of cancer, new cancer-resisting substance is continually developed.Especially, it is chemical sproof and press for for the material that the sort of cancer of using existing cancer-resisting substance not have satisfactory effect has a curative effect that those can overcome existing cancer-resisting substance.
According to As-Is, the present inventor has extensively screened microbial metabolites, as a result of, finds a kind of new active compound for anti tumor BE-13793C (12,13-dihydro-1,11-dihydroxyl-5H-indoles is (2,3-a) pyrrolo-(3,4-C) carbazole-5 also, 7 (6H)-diketone), and disclose it (referring to Japanese publication specification sheets No.20277/1991 and J.Antibiotics, 44,723-728 (1991)).
After this, the present inventor has prepared indoles and the pyrrolocarbazole compound with extremely strong anti-tumor activity by the chemically modified of BE-13793C, and it is open (referring to (PCT/WO91/18003).
In order to prepare and to have the more compound of powerful antitumor activity by previous disclosed indoles and pyrrolocarbazole antineoplastic compound being carried out chemically modified, the present inventor has synthesized a lot of indoles and pyrrolo carbazole derivatives, study their anti-tumor activity, as a result of, have now found that the series compound that available following general formula is represented is the new compound with extremely strong anti-tumor activity.
Thereby, the invention provides indoles and pyrrolo carbazole derivatives and their pharmacy acceptable salt by following general formula.
Wherein
R
1And R
2Represent hydrogen atom separately, low alkyl group, low-grade alkenyl; low-grade alkynyl, aryl, aralkyl or heterocyclic radical (low alkyl group; low-grade alkenyl, low-grade alkynyl, aryl; aralkyl and heterocyclic radical can each have 1 to 5 substituting group that is selected from following group: carboxyl, formamyl, sulfo group; amino, cyano group, list-lower alkyl amino; two-lower alkyl amino, hydroxyl and halogen atom), or formula-Y-R
3Group, and wherein Y represents carbonyl, thiocarbonyl group or alkylsulfonyl, R
3The expression hydrogen atom, low alkyl group, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, lower alkoxy, diazanyl, amino, virtue is amino, formamyl or heterocyclic radical (low alkyl group, cycloalkyl, cycloalkylalkyl, aryl, aralkyl and heterocyclic radical can each have 1 to 4 substituting group that is selected from following group: halogen atom, the hydroxyl of optionally being protected, amino, carboxyl, formamyl, cyano group and lower alkoxycarbonyl, but and low alkyl group list or two replacement amino and that each freedom of formamyl is optionally replaced, wherein the substituting group of low alkyl group can be selected from following groups: halogen atom, hydroxyl, amino, carboxyl, formamyl and lower alkoxycarbonyl); Or
R
1And R
2Combine expression low-grade alkylidene (low-grade alkylidene can have 1 to 4 substituting group that is selected from following group: amino, list-lower alkyl amino, two-lower alkyl amino, hydroxyl, carboxyl and alkylsulfonyl); Or
R
1And R
2Connected nitrogen-atoms combines can form heterocyclic radical (on the heterocycle low alkyl group that is optionally replaced can be arranged, the substituting group of low alkyl group is selected from: amino, hydroxyl, carboxyl and sulfo group),
G represents pentose or glycosyl,
X
1And X
2Represent hydrogen atom separately, halogen atom, amino, list-lower alkyl amino, two-lower alkyl amino, hydroxyl level, lower alkoxy, aralkoxy, carboxyl, lower alkoxycarbonyl or low alkyl group.
The term " rudimentary " that the present invention uses represents that the group that this term is related or the carbonatoms of compound are 6 or are less than 6 that preferred situation is 4 or is less than 4.
" low alkyl group " for containing 1 to 6 carbon atom straight chain or branched-chain alkyl, for example, and methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl etc.
" low-grade alkenyl " comprises the straight or branched thiazolinyl that contains 3 to 6 carbon atoms, for example, and propenyl, crotyl, 3-butenyl, 3-pentenyl, 4-hexenyl etc.
" low-grade alkynyl " can be for containing the straight or branched alkynyl of 3 to 6 carbon atoms, for example, and proyl, 2-butyne base, 3-butynyl, 3-pentynyl, 4-hexin base etc.
" cycloalkyl " comprises 3-to 6-unit cycloalkyl, for example, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" cycloalkyl low-grade alkyl " is the alkyl by cycloalkyl substituted, wherein, the implication of cycloalkyl and low alkyl group is distinguished as mentioned above, and its example has the cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, 1-cyclopropyl ethyl, 2-cyclopropyl ethyl, 1-cyclobutyl ethyl, 2-cyclobutyl ethyl, 1-cyclopentyl ethyl, 2-cyclopentyl ethyl, 1-cyclohexyl ethyl, 3-cyclohexyl propyl group, 3-cyclopentyl propyl group, 4-cyclohexyl butyl, 4-cyclopentyl butyl etc., preferably, cycloalkylalkyl contains 4 to 10 carbon atoms altogether.
" aryl " can be monocyclic and encircles more, and the aryl that contains 6 to 12 carbon atoms that can mention has phenyl, naphthyl and tetralyl.
" aralkyl " is the low alkyl group that aryl replaces, and wherein the implication of aryl and low alkyl group is distinguished as mentioned above, and the aralkyl that contains 7 to 15 carbon atoms that for example can mention has benzyl, styroyl, hydrocinnamyl, benzene butyl, benzene amyl group, menaphthyl, naphthalene ethyl.
" heterocyclic radical " comprises that 1 to 4 is selected from nitrogen, oxygen, and heteroatomic 5 yuan or 6 yuan of heterocyclic radicals of sulphur atom, for example, the aromaticity heterocyclic radical that can mention has pyrryl, furyl, thienyl ， oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl ， oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, furazan base, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and triazinyl; Non-aromaticity heterocycle has dihydro-thiophene base, tetrahydro-thienyl, pyrrolinyl, pyrrolidyl, imidazolidyl, imidazolinyl, piperidyl, piperazinyl oxazolinyl ， oxazolidinyl ， isoxazoline-3-yl isoxazole alkyl, thiazolinyl, thiazolidyl, the isothiazoline base, isothiazole alkyl, 1,2-dithiolane base, 1,3-dithiolane base, 1,2-dithiole base, 1,3-dithiole base, dihydro thiapyran base, tetrahydro thiapyran base, 1,4-dithiane base, 1,4-dithiadiene base, 1,4-oxathiin base and thio-morpholinyl.
The example of " the single lower alkyl amino " that can mention has methylamino-, ethylamino, third amino, isopropylamino, fourth amino, penta amino, own amino etc., the example of " the two lower alkyl amino " that can mention has dimethylamino, the ethyl methylamino-, diethylin, ethyl third amino, dipropyl amino, the butyl methylamino-, dibutylamino, butyl ethylamino, methylpent amino, hexyl methylamino-, the own amino of ethyl etc.
The amino that " virtue amino " expression is replaced by aryl, wherein aryl moiety as mentioned above, the amino example of virtue that can mention has phenylamino and naphthylamino.
" halogen atom " comprises fluorine atom, chlorine atom, bromine atoms and iodine atom.
As " low-grade alkylidene ", the example of the straight or branched alkylidene group that contains 1 to 6 carbon atom that can mention has methylene radical, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, inferior sec-butyl, pentylidene, isopentylidene, inferior neo-pentyl and hexylidene.
Foregoing (the low alkyl group)-O-of " lower alkoxy " expression low alkyl group part base, for example, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyl oxygen, hexyloxy etc.
Aforesaid (the lower alkoxy)-CO-of " lower alkoxycarbonyl " expression lower alkoxy part base, for example, methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, penta oxygen carbonyl, own oxygen carbonyl etc.
The lower alkoxy that " aralkoxy " expression is replaced by aryl, wherein the implication of aryl and lower alkoxy is distinguished as previously mentioned, and its example has benzyloxy, the benzene oxyethyl group, benzene propoxy-, α-naphthalene methoxyl group, β-naphthalene methoxyl group, naphthalene oxyethyl group, naphthane methoxyl group etc.
The protecting group example that can mention in " optionally substituted hydroxyl " is alkanoyl such as the ethanoyl that contains 2 to 6 carbon, propionyl and butyryl radicals; Aroyl such as benzoyl; Replace or unsubstituted aralkyl such as benzyl and 4-methoxybenzyl; The group of formation acetal such as acetonide etc.
" pentose base " and " hexose-based " represent that its hydroxyl can identical or different be selected from pentose base and the hexose-based that following group replaces by 1 to 3: hydrogen atom, low alkyl group, lower alkyl carbonyl oxygen base, lower alkoxy and amino, or its hydroxyl can be oxidized, and the example from pentose deutero-group that can mention has ribose, pectinose, wood sugar and 2-deoxyribose have allose from the example of the capable group of giving birth to of hexose, glucose, seminose, semi-lactosi, glucosamine, rich newborn osamine, the 2-deoxyglucose, 4-O-methyl glucoside, rhamnosyl and glucuronic acid.
Preferred compound is shown below in above-mentioned formula provided by the invention (I) compound
Wherein
R
11And R
21Represent hydrogen atom separately, low alkyl group, low-grade alkenyl, aryl, aralkyl; pyrryl ， oxazolyl ， isoxazolyl, thiazolyl, imidazolyl; pyridyl, pyrimidyl ， oxazolinyl ， oxazolidinyl; imidazolinyl, imidazolidyl, pyrrolidyl, piperazinyl; thiazinyl, thiazolidyl (low alkyl group, low-grade alkenyl, aryl; aralkyl and heterocyclic radical can have 1 to 5 to be selected from following substituting group: carboxyl, formamyl, cyano group and hydroxyl), or formula-Y-R
31Base, and wherein Y represents carbonyl, thiocarbonyl group or alkylsulfonyl, R
31The expression hydrogen atom, low alkyl group, (low alkyl group and aryl can have 1 to 4 to be selected from following substituting group to aryl: halogen atom, optionally Bao Hu hydroxyl, amino and carboxyl), amino, diazanyl, virtue is amino, lower alkoxy, formamyl, pyrryl ， oxazolyl isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl ， oxazolinyl ， oxazolidinyl, imidazolinyl, imidazolidyl, pyrrolidyl, piperazinyl, thiazinyl or thiazolidyl; Or
R
11And R
21Expression optionally has the alkylidene group of carboxyl altogether, or
R
11And R
21Combine with the nitrogen-atoms that is connected with them and can form pyrrolidyl, imidazolidyl, imidazolinyl, piperidino-(1-position only), piperazinyl (low alkyl group of optionally being got base by hydroxyl can be arranged on these heterocycles),
G
1Expression following formula group
Or
R wherein
7Expression hydrogen atom or low alkyl group, R
8Expression hydroxyl or amino, and
X
11And X
12Be connected in respectively the 1-of indoles and pyrrolocarbazole ring or 2-position and 10 or the 11-position on, represent halogen atom separately, hydroxyl, lower alkoxy or alkoxy aryl.
More preferred compound is represented with following formula
Wherein
R
12Expression hydrogen atom or low alkyl group,
R
22The expression hydrogen atom, (low alkyl group can have 1 to 5 to be selected from following substituting group to low alkyl group: carboxyl, formamyl; hydroxyl and cyano group); aryl, aralkyl (aryl and aralkyl can have 1 to 4 substituting group that is selected from hydroxyl and carboxyl), pyridyl; imidazolyl; imidazolinyl, thiazolyl, pyrrolidyl; piperazinyl, or formula-Y-R
32Group, and Y represents carbonyl, thiocarbonyl group or alkylsulfonyl, when Y is carbonyl or thiocarbonyl group, R
32The expression hydrogen atom, low alkyl group, (low alkyl group and aryl can have 1 to 4 to be selected from following substituting group to aryl: halogen atom; protected hydroxyl optionally, amino and carboxyl), amino; diazanyl, virtue is amino, lower alkoxy; formamyl, pyridyl, pyrimidyl; imidazolinyl; or pyrrolidyl, when Y is an alkylsulfonyl, R
32Expression low alkyl group or aryl; Or
R
12And R
22Expression has the alkylidene group of carboxyl altogether; Or
R
12And R
22Combine with the nitrogen-atoms that is connected with them and can form pyrrolidyl, piperidino-(1-position only) or piperazinyl (on these heterocycles the low alkyl group that is optionally replaced by hydroxyl can be arranged),
G
1, X
11And X
21Have and the identical definition of above-mentioned formula (Ia).
Usually, preferred G
1For
And preferred X
11And X
21Be respectively and be connected in indoles and pyrrolocarbazole ring 1-position and 11-position hydroxyl.
The form of the salt that The compounds of this invention can pharmaceutically be accepted exists.Such salt comprises inorganic acid addition salt, as, hydrochloric acid and sulfuric acid additive salt and organic acid additive salt, as, acetate, citric acid, tartrate and toxilic acid additive salt.In addition, if The compounds of this invention contains acidic-group, acidic-group also can an alkali metal salt, as sylvite and sodium salt; Alkaline earth salt is as magnesium salts and calcium salt; With organic alkali salt, exist as ethylamine salt and arginic acid salt.
The preparation process of formula disclosed by the invention (I) compound is as follows: with compound or its R shown in protected derivative of compound or its functional group shown in formula (II) or the formula (III) and the formula (IV)
13And R
23Functional group (if any words) protected derivatives reaction,
Wherein
Y represents hydrogen atom or is substituted or unsubstituted low alkyl group X
1, X
2With G definition same as described above is arranged;
R
13And R
23Represent hydrogen atom separately, low alkyl group, low-grade alkenyl; low-grade alkynyl, aryl, aralkyl or heterocyclic radical (low alkyl group; low-grade alkenyl, low-grade alkynyl, aryl; aralkyl and heterocyclic radical can have 1 to 5 to be selected from following substituting group: carboxyl, formamyl, sulfo group; amino, cyano group, list-lower alkyl amino; two-lower alkyl amino, hydroxyl and halogen atom), or formula-Y-R
3Group, wherein Y represents carbonyl, thiocarbonyl group or alkylsulfonyl, R
3The expression hydrogen atom, low alkyl group, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, lower alkoxy, diazanyl, amino, virtue is amino, formamyl or heterocyclic radical (low alkyl group, cycloalkyl, cycloalkylalkyl, aryl, aralkyl and heterocyclic radical can each have 1 to 4 and be selected from following substituting group: halogen atom, the hydroxyl of optionally being protected, amino, carboxyl, formamyl, cyano group and lower alkoxycarbonyl, but and amino and low alkyl group list that each freedom of formamyl is optionally replaced-or two-replacement, wherein the substituting group on the low alkyl group is selected from: halogen atom, hydroxyl, amino, carboxyl, formamyl and lower alkoxycarbonyl); Or
R
13And R
23The nitrogen-atoms that is connected with them combines formation heterocyclic radical (on the heterocycle low alkyl group that is optionally replaced can be arranged, the substituting group on the low alkyl group is selected from amino, hydroxyl, carboxyl and sulfo group); If desired, can remove the protecting group in the product and prepare compound shown in the general formula (Ic)
Wherein
R
13, R
23, X
1, X
2, G has definition same as described above; Perhaps work as R
13, R
23During the expression hydrogen atom, with the amino of above-mentioned formula (Ic) compound or its protected derivative of functional group
Formylation, alkylation, alkenylation, alkynylization, aralkylization, carbamoylation, the sulfo-carbamoylation, alkyl carbonylization or alkylsulfonylization, or with above-claimed cpd or row biology and the protected derivative condensation of formula (V) compound or its functional group,
OHC-R
6(V) wherein
R
6Expression hydrogen atom or carboxyl, or 1 to 4 substituent low alkyl group is optionally arranged, the substituting group on the low alkyl group is selected from: amino, list-lower alkyl amino, two-lower alkyl amino, hydroxyl, carboxyl and sulfo group, and, if desired, can remove the protecting group on the product; Perhaps, above-mentioned formula (Ic) compound (is worked as R
13And/or R
23Contain when two strong) or the protected derivative of compound or its functional group for preparing with formula (V) compound condensation of formula (Ic) compound in two keys reduce, and, if desired, remove the protecting group on the product; Work if desired can change into pharmacy acceptable salt with formula (I) compound of gained.
Wherein, the term alkylation, alkenylation, alkynylization, aralkylization, alkyl carbonylization and alkylsulfonylization can be explained widely, they represent that all can introduce corresponding R in the The compounds of this invention structure
1And R
2Substituent reaction, for example alkylation represents to introduce the reaction of the substituted and unsubstituted alkyl that the present invention includes.
Formula (II) or (III) compound are (after this; comprise the derivative that its functional group is introduced into) and formula (IV) compound is (after this; comprise the protected derivative of its functional group) reaction can carry out according to the reaction of known imide itself or acid anhydrides and hydrazine or hydrazine derivative; for example; can be when solvent-free or at the inert solvent, as N, in the dinethylformamide; carry out under the temperature between 0 ℃ and the solvent boiling point, its preferred temperature range is that room temperature arrives about 80 ℃.
Formula (IV) compound does not have special restriction for the consumption of formula (II) or formula (m) compound, can be according to the kind of compound, reaction conditionss etc. are in very wide range, but generally, for every mole of formula (II) or formula (III) compound, the consumption of formula (IV) compound is suitable at least 1 mole, preferable range is 1 to 10 mole, special preferable range is 3 to 5 moles, in addition, and when formula (IV) compound is liquid under temperature of reaction, can allow its excessive in large quantities use, for example, every mole of formula (II) or (III) compound use 10 to 40 moles, thus with it as solvent.
Thus, can obtain above-mentioned formula (Ic) compound that its functional group is suitably protected sometimes.
Thus obtained R
13And R
23The protected derivative of formula (Ic) compound or its functional group (hereinafter being often referred to (Ic-1) compound) of expression hydrogen atom can be by formylation, alkylation, alkenylation; alkynylization, aralkylization, carbamoylation; the sulfo-carbamoylation, alkyl carbonylization or alkylsulfonylization and obtain accordingly R at least
13And R
23In one of for non-hydrogen atom be formula (Ic) compound of the group that is defined as above.
The formylation of formula (Ic-1) compound can be undertaken by carbamyl method commonly used; for example; can be by with itself and formic acid; methane amide; dimethyl formamides etc. heat together and carry out; perhaps, the mixture of itself and formic acid and acid anhydrides is reacted in the solvent that has no adverse effects or reacts under solvent-free condition, or undertaken by other modes.
Formula (Ic-1) compound and formic acid, methane amide, the reaction of dimethyl formamide etc. is carried out in the temperature range of solvent boiling point at 30 ℃ usually, but if desired, also can carry out being higher or lower than under the said temperature, and the reaction times is generally 30 minutes to 2 days.Preferably, this reaction is carried out in acid catalyst example hydrochloric acid or sulfuric acid usually.
Use the formylation of formic acid and acid anhydride mixture to carry out to the room temperature lesser temps under at-5 ℃ usually, still if desired, also can carry out being higher or lower than under this temperature.In addition, the reaction times is 10 minutes to 5 hours, but if desired, also can be longer or shorter.
The alkylation of formula (Ic-1) compound, alkenylation, alkynylization and aralkylization can be according to known methods itself, for example, use alkylating agent, alkenyl agent, alkynyl agent or aralkyl agent such as haloalkane, haloolefin, halo alkynes, the halo aralkyl, the alkyl methanesulfonates, alkenyl methanesulfonates, aralkyl methanesulfonates, the alkyl toluene sulphonate, the reaction of aralkyl tosylate; Or with aldehydes or ketones and its condensation and the method for gained condenses of reducing; Or similar approach is carried out.Reduction reaction herein can be according to using formic acid, and the method for metal or metal hydride or common method are carried out as the catalytic reduction method with palladium-carbon.
The carbamylation of formula (Ic-1) compound and thiocarbamoylization can be by it and corresponding isocyanic ester or isothiocyanic acid ester solvent-free or react in suitable solvent and carry out.Temperature of reaction can be preferably about 0 to about 50 ℃ approximately-20 ℃ in the solvent boiling point scope.
The alkyl carbonylization of formula (Ic-1) compound available it carry out in method solvent-free or that in suitable solvent, react with corresponding carboxylic acid halides or acid anhydrides.Reaction usually approximately-5 ℃ is being carried out to the temperature range of solvent boiling point in, if desired, reacts also and can carry out being lower than under the temperature of this temperature.
Usually use with respect to excessive slightly carboxylic acid halides or the acid anhydrides of formula (Ic-1) compound, if desired, also can use still less or more consumption, usually, the reaction times can be 30 minutes to two days.
The sulfonylation of formula (Ic-1) compound can with it with as the reagent of corresponding organic sulfonic acid acid anhydride or organic sulfonic acid halide have or alkali-free in the presence of react and carry out.Usually, temperature of reaction can be approximately-10 ℃ in about 50 ℃ scope, but as need to be higher or lower than this temperature, and the reaction times is generally 30 minutes to 3 days.Organic sulfonic acid acid anhydride or organic sulfonic acid halide usually will excessive slightly uses, but also can use more or less amount.
In addition; the reaction of formula (Ic-1) compound and above-mentioned formula (V) compound (comprising the protected derivative of its functional group) is called as Schiff's base and forms reaction; for example often can be in to reaction inert solvent; for example in tetrahydrofuran (THF); 0 ℃ of temperature range to solvent boiling point, preferably under room temperature to 50 ℃, carry out, the reaction times is 30 minutes to 2 days usually; but if desired, can be longer or shorter.
Formula (V) compound does not have strict restriction with respect to the consumption of formula (Ic-1) compound, and the suitable consumption of formula (V) compound is that every mole of formula (Ic-1) compound uses 1 to 50 mole of formula (V) compound usually, is preferably 3 to 10 moles especially.
To carry out catalytic hydrogenation with palladium-carbon etc. by the hydrazone compounds that above-mentioned reaction obtains or other method obtains R
1Or R
2Formula (I) compound of expression hydrogen atom.
In the aforesaid method, the protecting group in the protection of starting compound functional group and the gained compound remove known commonly used the carrying out of available chemical field with optional method.
In addition, the separation of the compound that above-mentioned reaction produces and purifying can be according to the known methods in Synthetic Organic Chemistry field itself, as, the precipitator method, solvent extration, recrystallization method, chromatography waits carries out.
In aforesaid method as the formula (II) of starting raw material but compound shown in the compound through type (VI) or the protected derivative of its sense
Wherein
X
1, X
2With Y implication with aforementioned usefulness is mutually arranged, glucosideization prepare, its Chinese style (VI) compound can prepare by known method itself.(with reference to J.Chem.Soc.Perkin Transactions I.pp2475-2480 (1990))
The glucosideization of formula (VI) compound or its protected derivative of functional group can be by known method own (with reference to J.Am.Chem.Soc.60; 2559 (1938)); for example; by it is used protected pentose of hydroxyl or hexose reactive derivative; as 1-bromo-2,3,4; the tetra-acetylated glucose of 6-O-; use the activator mercury cyanide, silver carbonate, silver suboxide etc.; be preferably silver suboxide; at aprotic solvent, as benzene, in toluene or the methylene dichloride; at 0 ℃ to 100 ℃, be preferably under about 80 ℃ temperature condensation and carry out.
In addition, also can come preparation formula (II) compound according to disclosed method among the aforementioned PCT/WO91/18003.
In addition, formula (III) compound also can be by preparing with the protected capable biology of the resulting formula of alkaline purification (II) compound or its functional group.
Preferred alkali is potassium hydroxide aqueous solution, and alkaline purification is at room temperature carried out usually, still, also is heated to 50 ℃ sometimes and carries out.
If desired, the neutralization of reaction mixture or acidifying can use hydrochloric acid to carry out, thereby it is possible that formula (III) compound precipitates as crystallization.
Following pharmacological evaluation embodiment shows that formula provided by the invention (I) compound has extremely strong antitumor action.
(1) to the result of treatment of mouse tumor (P388)
The compounds of this invention is listed in table 1 and 2 result of treatment of mouse tumor (P388).
Table 1
Example 2 compounds are to the effect tumour of P388
(1)Dosage
(2), i.p MST
(3)(my god) T/C (%)
(4)
(mg/kg/ injection)
0 12.3±1.06 100
1 15.8±0.84 128P388 3 17.8±1.92 145
10 ＞26.4±18.82 ＞245
30 ＞42.2±24.38 ＞343
100 ＞47.2±18.90 ＞384
Table 2
Example 5 compounds are to the effect tumour of P388
(1)Dosage
(2), i.p MST
(3)(my god) T/C (%)
(4)
(mg/kg/ injection)
0 12.3±0.95 100
1 16.8±0.84 137P388 3 17.8±1.92 145
10 ＞26.2±10.18 ＞213
30 ＞23.4±9.74 ＞190
100＞36.4 ± 8.05＞296 (table 1 and 2 footnote) (1) tumor inoculation: with 10
6The inoculation of cancer cells intraperitoneal.(2) dosage: behind the tumor inoculation one to ten day, every day, intraperitoneal was administered once.(3) MST: expression survival fate.(4) T/C (%): (treatment group, MST/ control group MST) * 100 (5) standards: if T/C 〉=125 then can be evaluated test-compound and be had remarkable antitumous effect at this dosage.
(2) to mouse leukemia cell inhibition of proliferation activity determination method:
100 μ l are contained 3 * 10
3The cell culture medium of mouse leukemia cell (P388) (10% contains the Bovine Placenta blood serum medium (10%fetalbovine serum-containing-RPMI-1640medium) of RPMI-1640) is put into the miniature plate in 96 holes, at 5%CO
2In, it was cultivated 24 hours at 37 ℃, be that the testing liquid that contains test compound of 10 μ 1 adds respectively with every part, then, at 5%CO
2In, this cell was cultivated 24 hours at 37 ℃ again.0.5% Thiazolyl blue (Thiazoyl Blue) of 10 μ l is added broth culture, be inoculated among the 5%CO, carried out 2 hours at 37 ℃, to realize enzyme reaction, add 20% sodium lauryl sulphate with stopped reaction, be seeded in 37 ℃ and carry out 4 hours dyestuffs to be decomposed to form again, measurement 550nm place absorbs and compares with control group.The result is presented at table 3.
Table 3
To mouse leukemia cell P388 inhibition of proliferation activity test compound 50% inhibition concentration (IC
50, μ M) and example 1 compound＜0.030 example, 2 compounds, 0.29 example, 3 compounds, 0.065 example, 4 compounds, 0.096 example, 5 compounds, 0.28 example, 6 compounds, 0.059 example, 7 compounds, 0.091 example, 8 compounds, 0.30 example, 9 compounds, 0.028 example, 10 compounds, 0.46 example, 11 compounds＜0.026 example, 12 compounds, 0.042 example, 13 compounds, 0.22 example, 14 compounds＜0.027 example, 15 compounds, 0.31 example, 17 compounds, 0.044 example, 22 compounds, 0.11 example, 23 compounds＜0.025 example, 24 compounds, 0.001 example, 25 compounds, 0.048 example, 27 compounds, 0.027 example, 28 compounds＜0.029 example, 29 compounds, 0.005 example, 30 compounds, 0.003 example, 31 compounds, 0.011 example, 33 compounds, 0.11 example, 34 compounds, 0.019 example, 35 compounds, 0.17 example, 36 compounds, 0.002 example, 37 compounds 0.095
Obviously can see that from above-mentioned pharmacological evaluation The compounds of this invention shows very strong anti-tumor activity, can be used as control and ward off disease, particularly treat the antineoplastic agent of cancer.When The compounds of this invention was used for this purpose, it often was formulated into the pharmaceutical preparation that contains significant quantity The compounds of this invention and pharmaceutically acceptable carrier or thinner.
Can select various form of medication to use The compounds of this invention, for example, can be medicinal preparation for oral administration such as tablet, capsule, pulvis, granule or liquid preparation perhaps are aseptic non-enteron aisle liquid preparation such as solvent or suspension, perhaps are suppository, ointment etc.
The solid preparation that can prepare has tablet, capsule, and granule or pulvis also can use suitable additive in the preparation, and additive is normally used, comprises carbohydrate such as lactose and glucose; Starch such as corn, wheat and rice; Lipid acid such as stearic acid; Inorganic salt such as neusilin hydrochlorate and anhydrous ca phosphate; Synthetic macromolecule such as polyvinylpyrrolidone and polyalkylene glycol; Soap such as calcium stearate and Magnesium Stearate; Alcohols such as Stearyl alcohol and phenylcarbinol; Synthetic cellulose derivative such as methylcellulose gum, carboxymethyl cellulose, ethyl cellulose and Vltra tears; Also have gelatin, talcum, vegetables oil, gum arabic etc. in addition.
Such as tablet, capsule, the solid preparation of granule and pulvis generally contains the effective constituent of 0.1-100 weight percent, is preferably the 5-100 weight percent.
The liquid preparation that is prepared to has suspension agent, syrup, and injection or drops, the suitable additive that uses in liquid preparation is generally water, alcohol or vegetables oil such as soybean oil, peanut oil and sesame oil.
Especially, with intramuscular injection, in intravenous injection or the medication of subcutaneous injection form parenteral route, suitable solvent comprises, as distilled water for injection, the lidocaine aqueous solution (being used for intramuscular injection), physiological saline, D/W, ethanol, polyoxyethylene glycol, used for intravenous injection liquid (as citric acid and sodium citrate aqueous solution etc.), electrolyte solution (being used for vein point annotates and intravenous injection) etc., and their mixture.
Except component by the dissolved form in advance, these injections also can be made into the powder of itself or add the form of appropriate addn therein, in use dissolving.Such injection contains the 0.1-10 weight percent usually, is preferably the active ingredient of 1-5 weight percent.
In addition, suspension agent, syrup, or the liquid preparation of other oral administrations contains the active principle of 0.5-10 weight percent usually.
The suitable dose of The compounds of this invention can be according to the classes of compounds of using, the kind of pharmaceutical composition and administration number of times, processed concrete position, the degree of disease, patient's year order, doctor's diagnosis, kind of tumour etc. and changing, but, as a kind of approximate test, the dosage of each per day for adults, oral administration is 10 to 500mg, parenteral administration, preferably, intravenous dosage is 10 to 100mg.Administration number of times depends on medication and symptom, is every day 1 to 5 time.In addition, also can take as the administration at intermittence.As administration in per two days or administration in per three days.
The following example is of the present invention in order more clearly to describe, rather than limitation of the present invention.
Embodiment A
Compound shown in the following formula
With 3.4g12,13-dihydro-1,11-dihydroxyl-13-(β-D-glucopyranosyl-5H indoles also (2,3-a) pyrrolo-(3,4-c) carbazoles-5,7 (6H)-diketone is dissolved in the 120ml10% potassium hydroxide aqueous solution, and it was at room temperature stirred 2 hours, add 120ml2N hydrochloric acid neutralization reaction solution, the red crystallization that is settled out is filtered, washing with water also, drying obtains the 3.0g title compound.FAB-MS(m/z)：520(M)
+，521(M+H)
+ 1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：3.42(1H，m)，3.56-3.70(2H，m)，3.76(1H，m)，3.95-4.10(2H，m)，4.95(1H，d，J＝4.6Hz)，5.24(1H，d，J＝5.4Hz)，5.32(1H，dd，J＝4.9，5.1Hz)，7.06(2H，dd，J＝7.6，7.8Hz)，7.09(1H，d，J＝8.0Hz)，7.20(1H，d，J＝7.8Hz)，7.40(1H，d，J＝7.8Hz)，8.36(1H，d，J＝7.6Hz)，8.51(1H，d，J＝7.6Hz)，10.13(1H，s)，10.52(1H，s)，11.11(1H，s)
Embodiment B
Compound shown in the following formula
50mg rebeccamycin is dissolved in 5ml N, in the dinethylformamide, adds 5ml 2N aqueous sodium hydroxide solution, and this mixture was stirred 3 hours at 80 ℃.In reaction soln, add 60ml water,, yellow mercury oxide is leached and collects with ice-cooled this mixture.With silica gel column chromatography on it (internal diameter 1.5cm, long 45cm), after washing with chloroform, carry out wash-out, and the flow point that will contain required product is concentrated into dried with chloroform-tetrahydrofuran (THF) (10: 1).Obtain the 6.4mg title compound with chloroform washing gained yellow powder.
Rf value: 0.51 (Merck Co. production, Kiesel gel 60F
254Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF): acetate=10: 1: 1: 0.2) FAB-MS (m/z): 571[M+H]
+ 1H-NMR (300MHz, DMSO-d
6), δ (ppm): 10.9 (1H, s), 9.07 (1H, d, J=7.8Hz), 8.92 (1H, d, J=7.8Hz), 7.78 (2H, t, J=7.8Hz), 7.53 (1H, d, J=7.8Hz), 7.50 (1H, d, J=7.8, Hz), 7.03 (1H, d, J=8.9Hz), 3.96 (2H, m), 3.87 (1H, m), 3.61 (3H, s), 3.54-3.73 (3H, m)
Embodiment 1
Compound shown in the formula (1)
With 3.51g 12,13-dihydro-1,11-dihydroxyl-13-(β-D-glucopyranosyl)-5H-indoles also (2,3-a) and pyrrolo-(3,4-c) carbazole-5,7 (6H)-diketone are dissolved in that (Wako Pure ChemicalIndustries Ltd.) at room temperature carries out reaction 2 hours in the 8ml hydrazine hydrate.After the reaction, add the 180ml pure water, solution PH is adjusted to 5.0, this mixture with fully cooling of ice, is leached the gained precipitation, obtain title compound shown in the 3.51g formula (1) with pure water washing and drying under reduced pressure with concentrated hydrochloric acid.(productive rate: 97%)
FAB-MS(m/z)：535(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.9
(1H，brs)，10.4(1H，s)，10.0(1H，s)，8.72
(1H，d，J＝7.8Hz)，8.54(1H，d，J＝7.8Hz)，7.
19(2H，t，J＝7.8Hz)，7.19(2H，t，J＝7.8Hz)，
7.05(1H，d，J＝9.3Hz)，7.02(H，d，J＝7.
8Hz)，7.00(1H，d，J＝7.8Hz)，5.42(1H，brd，
J＝5.8Hz)，5.35(1H，brs)，5.22(1H，brd，J＝
4.4Hz)，4.96(2H，brs)，4.91(1H，brd，J＝5.
3Hz)，4.01(2H，m)，3.73(1H，m)，3.63(2H，
m)，3.39(1，m)
Embodiment 2
Compound shown in the formula (2)
3.47g embodiment 1 gained compound is dissolved in 20ml N, in the dinethylformamide (DMF), under the room temperature, the Glyoxylic acid hydrate solution (Sigma Co.) of 20ml 100mg/ml is added this solution while stirring in batches, form precipitation thus and also be frozen into glue.Add the 200ml pure water in addition again, use ice-cooled reaction soln, leach the gained precipitation, obtain (the productive rate: FAB-MS (m/z) 100%): 591 (M+H) of title compound shown in the 3.85g formula (2) with pure water washing and drying under reduced pressure
+ 1H-NMR (400MHz, DMSO-d
6), δ (ppm): 11.1 (1H, brs), 10.5 (1H, brs), 10.1 (1H, brs), 9.01 (1H, s), 8.69 (1H, d, J=7.8Hz), 8.53 (1H, d, J=7.8Hz), 7.23 (2H, t, J=7.8Hz), and 7. 10 (1H, d, J=9.3Hz), 7.06 (1H, d, J=7.8Hz), 7.04 (1H, d, J=7.8Hz), 5.44 (1H, brs), 5.34 (1H, brs), 5.24 (1H, brs), (4.95 1H, brd, J=5.9Hz), 4.02 (2H, m), 3.76 (1H, m), 3.64 (2H.m) .3.40 (1H.m)
Embodiment 3
Compound shown in the formula (3)
24mg embodiment 1 gained compound dissolution at 0.5ml N, in the dinethylformamide (DMF), under the room temperature, is added 0.2ml 15% amber rose acid semialdehyde (Aldrich Chemical Co.) while stirring, after one hour, add the 5ml pure water again.Behind ice-cooled reaction soln, leach the gained precipitation, washing also with pure water, drying under reduced pressure obtains title compound shown in the 25.3mg formula (3).(productive rate: FAB-MS (m/z) 91%): 619 (M+H)
+ 1H-NMR (400MHz.DMSO-d
6). δ (ppm): 12.1 (1H, brs), 11.0 (1H, brs), 10.4 (1H1, brs), 10.0 (1H, brs), 8.69 (1H, brs), 8.68 (1H, d, J=7.8Hz), 8.51 (1H, d, J=8.3Hz), 7.19 (2H, t.J=7.8Hz), 7.07 (1H, d, J=9.3Hz), 7.04 (1H, d, J=7.8Hz), 7.01 (1H, d, J=7.8Hz), 5.43 (1H, brd, J=5.4Hz), 5.33 (1H, brs), 5.22 (1H, brs), 4.93 (1H, brd, J=4.9Hz), 4.01 (2H, m), 3.74 (1H, m), 3.63 (2H, m), 3.40 (1H, m)
Embodiment 4
Compound shown in the formula (4)
With 511mg rebeccamycin (J.Antibiotics 40, the described compound of 668-678 (1987)) be dissolved in the 3ml hydrazine hydrate (Wako Pure Chemical Industries, Ltd.) in, solution was at room temperature placed one hour.Add the 200ml pure water, leach the gained precipitation,, obtain title compound 6-N-amino-rebeccamycin shown in the 497mg formula (4) with washing of 100ml pure water and drying under reduced pressure.(productive rate: FAB-MS (m/z) 95%): 585 (M+H)
+ 1H-NMR (400MHz, DMSO-d
6), δ (ppm): 10.64 (1H, brs), 9.24 (1H, d, J=7.8Hz), 9.07 (1H, d, J=7.8Hz), 7.70 (2H, t, J=7.8Hz), 7.45 (1H, d, J=7.8Hz), 7.42 (1H, d, J=7.8Hz), 6. 93 (1H, d, J=8.8Hz), 5.42 (1H, d, J=5.8Hz), 5.33 (1H, t, J=5.4Hz), 5.03 (3H, brs), 3.97 (2H, m), 3.84 (1H, m), 3.59 (3H, s), 3.50～3. 70 (3H, m)
Embodiment 5
Compound shown in the formula (5)
(method A)
5g embodiment 1 gained compound dissolution at 60ml N, in the dinethylformamide, is added the 1.8ml concentrated hydrochloric acid, this mixture 60 ℃ of heating 4 hours, is added the 0.8ml concentrated hydrochloric acid again, this mixture is warm 16 hours at 37 ℃.It is mixed with 1 liter of ethyl acetate, and mixture washs successively with 2% sodium bicarbonate aqueous solution and water, then with anhydrous sodium sulphate with ethyl acetate layer dehydration and be concentrated into driedly, obtain the 3.3g orange powder.It is dissolved in methyl alcohol and goes up Sephadex LH20 column chromatography (interior through 3cm, long 54cm uses methanol-eluted fractions), and the flow point that will contain the product of wanting is concentrated into dried, obtains title compound shown in the 2413.6mg formula (5), is orange powder.(method B)
25.9mg embodiment A gained compound dissolution at 0.5ml N, in the dinethylformamide, is added the 15.0mg formyl hydrazine, this mixture was stirred 2 hours at 70 ℃.It is mixed with the 70ml ethyl acetate, and water (20ml) washs this mixture.With ethyl acetate layer dehydration and be concentrated into driedly, obtain 26.9 gram orange powders with anhydrous sodium sulphate.It is dissolved in the methyl alcohol and goes up Sephadex LH20 column chromatography (internal diameter 1.5cm, long 48cm, methanol-eluted fractions), the flow point that will contain the product of wanting is concentrated into dried, obtains title compound shown in the 16.3mg formula (5), is orange powder.
Rf value: 0.35 (Merck Co. production, Kiesel gel 60F
254Developping agent, chloroform-methanol-tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：562(M)
+
1H-NMR(400MHz.DMSO-d
6)，δ(ppm)：11.0
(1H，brs)，10.8(1H，s)，10.4(1H，s)，10.0
(1H，s)，8.64(1H，d，J＝8.3Hz)，8.47(1H，d，
J＝8.3Hz)，8.44(1H，s)，7.21(2H，t，J＝7.
8Hz)，7.06(1H，d，J＝9.7Hz).7.05(1H，d，J＝ 7.8Hz)，7.02(1H，d，J＝7.8Hz)，5.43(1H，d， J＝5.8Hz)，5.36(1H，brs)，5.22(1H，d，J＝5. 4Hz)，4.92(1H，d，J＝5.4Hz)，4.02(2H，m)， 3.75(1H，m)，3.62(2H，m)，3.39(1H，m)
Embodiment 6
Compound shown in the formula (6)
30ml acetate and 2ml diacetyl oxide are joined in the 510mg embodiment 1 gained compound, and be heated to 90 ℃ and this is changed thing be dissolved in wherein.Add water and make mixture reach 300ml, and reaction product is adsorbed on (internal diameter 3cm, long 13.5cm) on the Diaion HP20 post, after 600ml washing post, use the 300ml methanol-eluted fractions.Concentrate meoh eluate to doing, residue is dissolved in the 50ml methyl alcohol, this solution concentration is arrived about 5ml.Add the 100ml ethyl acetate.4 ℃ of placements are spent the night, and leach orange precipitation, obtain title compound shown in the 426mg formula (6).
Rf value: 0.43 (Merck Co. production, Kiesel gel 60F
254Developping agent, chloroform-methanol-tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：576(M)
+
1H-NMR(400MHz、DMSO-d
6)、δ(ppm)：11.0 (1H、s)、10.7(1H、s)、10.4(1H、brs)、10.05 (1H、s)、8.64(1H、d、J＝7.8Hz)、8.47(1H、d、 J＝7.8Hz)、7.20(2H、t、J＝7.8Hz)、7.01-7. 06(3H、m)、5.35-5.45(2H、m)、5.23(1H、 brs)、4.92(1H、brs)、4.02(2H、m)、3.74 (1H、m)、3.58-3.70(2H、m)、3.40(1H、m)、2. 10(3H、s)
Embodiment 7
Compound shown in the formula (7)
72.5mg the compound of embodiment 1 gained is dissolved in 8ml tetrahydrofuran (THF) and the 5ml methanol mixture, adds the formalin of 140 μ l 2N hydrochloric acid and 13.2 μ l 37%, in room temperature mixture is stirred 2 hours, is concentrated into dried.It is dissolved in the 5ml N that contains 80mg10% palladium/carbon, in the dinethylformamide, mixture is used hydrogen reducing 2 hours in room temperature, use diatomite filtration.Add the 80ml ethyl acetate in gained filtrate, mixture is used 2% sodium bicarbonate aqueous solution and water washing continuously, with gained ethyl acetate layer dehydration, and is concentrated into dried 28.8mg orange powder.It is dissolved in the small amount of methanol, and this solution carries out column chromatography (internal diameter 1.5cm, long 90cm uses methanol-eluted fractions) with Sephadex LH-20.Get the title compound shown in the 17.1mg formula (7), be orange powder.
The Rf value: 0.49 (uses the silica gel 60F of Merck Co.
254(Kiesel gel60F
254); Developping agent, chloroform-methanol-tetrahydrofuran (THF)-acetate=20: 10: 10: 1).
FAB-MS(m/z)：549(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.9 (1H，s)，10.4(1H，s)，9.98(1H.s).8.72 (1H，d，J＝7.8Hz)，8.54(1H，d.J＝7.8Hz)，7. 19(2H，t，J＝7.8Hz)，7.00-7.06(3H，m)，5. 73(1H，q，J＝5.4Hz)，5.43(1H，d，J＝5.7Hz). 5.35(1H，brs)，5.22(1H，d，J＝5.4Hz)，4.90 (1，d，J＝5.4Hz)，3.96-4.03(2H，m)，3.74 (1H，m)，3.58-3.70(2H，m)，3.40(1H，m)，2. 74(3H，d，J＝5.4Hz)
Embodiment 8
Compound shown in the formula (8)
The compound that 500mg embodiment 2 makes is dissolved in 6ml N, in the dinethylformamide (DMF), add 75mg 10% palladium/carbon (Pd-C), hydrogenation is 3.5 hours under room temperature and stirring, and reaction mixture is with spreading diatomaceous filter paper filtering to remove Pd-C, in filtrate, add 150ml water, with 1N NaOH mixture is transferred to pH5, use ethyl acetate extraction (200ml * 5) again, concentrate ethyl acetate layer, filter and collect the crystal that settles out, get the title compound shown in the 182.3mg formula (8).
FAB-MS(m/z)：593(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：12.6 (1H，brs)，10.9(1H，s).10.4(1H，s)，10.0 (1H，s)，8.69(1H，d，J＝8.3Hz)，8.52(1H，d， J＝7.8Hz)，7.18(2H，t，J＝7.8Hz)，6.99～7. 05(3H，m)，5.90(1H，brs)，5.42(1H，d，J＝5. 4Hz)，5.35(1H，t，J＝5.4Hz)，5.21(1H，d，J＝ 4.9Hz)，4，89(1H，d，J＝5.4Hz)，4.03(2H， m)，3.83(2H，s)，3.74(H，m)，3.63(2H，m)， 3.39(1H.m)
Embodiment 9
Compound shown in the formula (9)
In 501.7mg embodiment A gained compound and 501.7mg Urea,amino-hydrochloride, add 30ml methyl alcohol, add the 0.325ml triethylamine then, mixture heating up was refluxed 8 hours.It is dried that reaction soln is concentrated into, and adds 300ml methylethylketone (MEK) and 200ml water and extract, and adds 300ml MEK in the water layer again and extract once.MEK is also laminated, be concentrated into driedly, add 300ml methyl alcohol in the residue and make its dissolving, with this solution with Sephadex LH-20 column chromatography (3 * 28cm), use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, get the title compound shown in the 461mg formula (9), be the crystalline powder of redness.
Rf value: 0.15 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：577(M)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：11.0 (1H，s)，10.4(1H，s)，10.0(1H，s)，8.68 (1H，s，J＝7.8Hz)，8.66(1H，brs)，8.51(1H， d，J＝7.8Hz)，7.20(2H，t，J＝7.8Hz)，7.01～ 7.07(3H，m)，6.41(2H，brs)，5.44(1H，d，J＝ 5.4Hz)，5.38(1H，brs)，5.23(1H，d，J＝4. 9Hz)，4.91(1H.brs)，4.00～4.09(2H，m)，3. 75(1H，m)，3.60～3.68(21，m)，3.39(1H.m)
Embodiment 10
Compound shown in the formula (10)
In 22mg embodiment A gained compound and 20mg thiosemicarbazide, add 4ml methyl alcohol, mixture heating up was refluxed 22 hours, reaction soln is concentrated into dried, residue is dissolved in the 4ml methyl alcohol, this solution carries out column chromatography (1.8 * 35cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 10.7mg formula (10).
Rf value: 0.29[silica gel 60F
254(Kiesel gel 60F
254, Merck Co.) and developping agent; Chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1]
FAB-MS(m/z)：594(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：11.0
(1H，s)，10.4(1H，brs)，10.1(1H，brs)，9.
73(1H，brs)，8.65(1H，d，J＝7.8Hz)，8.49
(1H，d，J＝7.8Hz)，8.27(2H，s)，7.21(2H，t，
J＝7.8Hz)，7.01～7.12(3H，m)，5.45(1H，
brs)，5.37(1H，brs)，5.24(1H，brs)，4，91
(1H，brs)，3.97～4.10(2H，m)，3.74(1H，m)，
3.62(2H，m)，3.40(1H，m)
Embodiment 11
Compound shown in the formula (11)
9.5mg the compound that embodiment 1 makes is dissolved in the 2ml tetrahydrofuran (THF) (THF); In solution, add 30mg methylsulfonic acid acid anhydride (Aldrich Chemical Co.), mixture was left standstill under room temperature 48 hours, reaction soln is concentrated into dried, residue is dissolved in the 2ml methyl alcohol, carry out column chromatography (1.8 * 34cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, the title compound shown in the 8.3mg formula (11)
Rf value: 0.48 (silica gel 60F
254, (Kiesel gel 60F
254, MerckCo.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：612(M)
+
1H-NMR(400MHz.DMSO-d
6)，δ(ppm)：11.0
(1H，s)，10.5(1H，brs)，10.4(1H，s)，10.1
(1H，s)，8.67(1H，d.J＝7.9Hz)，8.50(1H，d，
J＝7.7Hz)，7.22(2H，t，J＝7.6Hz)，7.02～7.
07(3H，m)，5.43(1H，d，J＝5.8Hz)，5.36(1H，
brs)，5.22(1H，d，J＝5.2Hz)，4.89(1H，d，J＝
4.8Hz)，4，03(2H，m)，3.75(1H，m)，3.63
(2H，m)，3.40(1H，m)
Embodiment 12
Compound shown in the formula (12)
Add 1ml methyl alcohol in the 11.7mg embodiment 1 gained compound and the 2ml tetrahydrofuran (THF) is made solution, toward wherein adding 0.1ml third acid anhydride (Aldrich Chemical Co.), in room temperature mixture was stirred 4 hours, in reaction soln, add 2ml water and 3ml methyl alcohol, mixture was left standstill 30 minutes and be concentrated into dried, add 3ml methyl alcohol and make solution, this solution carries out column chromatography (1.8 * 30cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, the title compound shown in the 6.2mg formula (12).
Rf value: 0.55 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：11.0
(1H，s)，10.6(1H，brs)，10.4(1H，brs)，10.
0(1H，s)，8.64(1H.d.J＝7.8Hz)，8.47(1H，
d，J＝7.8Hz)，7.20(2H，t，J＝7.8Hz)，7.00～
7.08(3H，m)，5.30～5.45(2H，m)，5.21(1H，
m)，4.92(1H，m)，4.02(2H，m)，3.75(1H，m)，
3，62(2H，m)，3.38(1H，m)，2.39(2H，q，J＝9.
3Hz)，1.16(3H，t，J＝7.3Hz)
Embodiment 13
Compound shown in the formula (13)
9.9mg the compound that embodiment 1 makes is dissolved in the 2ml tetrahydrofuran (THF), add 0.06ml trifluoroacetic anhydride (Aldrich Chemical Co.), mixture was placed 15 minutes in room temperature, in reaction mixture, add 2ml water, mixture is concentrated into dried, add 2ml water and the 10ml ethyl acetate extracts, be concentrated into the gained ethyl acetate layer dried.The thick product of gained is dissolved in the 3ml methyl alcohol, with Sephadex LH-20 carry out column chromatography (1.8 * 30cm), use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 9.5mg formula (13).
Rf value: 0.53 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：630(M)
+
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：12.7
(1H，brs)，11.0(1H，brs)，10.5(1H，brs)，
10.1(1H，brs)，8.61(1H，d，J＝7.6Hz)，8.45
(1H，d，J＝7.9Hz)，7.21(2H，t，J＝7.6Hz)，7.
02～7.07(3H，m)，5.42(1H，d，J＝5.8Hz)，5.
35(1H，brs)，5.21(1H，brs)，4.91(1H，d，J＝
5.5Hz)，4.02(2H，m)，3.76(1H，m)，3.61
(2H，m)，3.39(1H，m)
Embodiment 14
Compound shown in the formula (14)
4ml methyl alcohol and 4ml benzene is added in the 31.6mg embodiment 8 prepared compounds makes solution.Add 0.15ml trimethyl silyl diazomethane (10% hexane solution, Tokyo Kasei Co.), mixture was placed under room temperature 10 minutes, be concentrated into the methyl esters of dried 29.3mg embodiment 8 gained compounds.It is dissolved in the 5ml methyl alcohol, add the 0.6ml strong aqua, in stirring at room mixture 16 hours, reaction soln is concentrated into dried, add 3ml methyl alcohol in the residue and make solution, with this solution with Sephadex LH-20 carry out column chromatography (1.8 * 36cm), use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, title compound shown in the 16.9mg formula (14)
Rf value: 0.22 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：592(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.9
(1H，s)，10.4(1H，brs)，10.0(1H，brs)，8.
69(1H，d，J＝7.3Hz)，8.52(1H，d，J＝8.3Hz)，
7.77(1H，brs)，7.39(1H，brs)，7.19(2H，t，
J＝7.8Hz)，6.98～7.05(3?H，m)，6.25(1H，t，J
＝3.9Hz)，5.41(1H，d，J＝5.4Hz)，5.35(1H，
brs)，5.20(1H，d，J＝5.4Hz)，4.87(1H，d，J＝
5.4Hz)，4.02(2H，m)，3.74(1H，m)，3.68～3.
70(4H，m)，3.39(1H，m)
Embodiment 15
Compound shown in the formula (15)
2ml methyl alcohol joined in 11mg embodiment A gained compound and the 10mg 2-hydrazino pyridine (Aldrich Chemieal Co.) make solution,, reaction soln is concentrated into dried this vlil 1.5 hours; Add 30ml water and 50ml ethyl acetate, with 1N hydrochloric acid water layer being transferred to pH5 extracts, be concentrated into the gained ethyl acetate layer dried, the thick product of gained is dissolved in the 2ml methyl alcohol, carry out column chromatography (1.8 * 36cm) with Sephadex LH20, use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 10mg formula (15).
Rf value: 0.46 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：612(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：11.0
(1H，s)，10.4(1H，s).10.0(1H，s)，9.34
(1H，s)，8.65(1H，d，J＝8.3Hz)，8.48(1H，d，
J＝7.8Hz)，7.95(1H，d，J＝4.9Hz)，7.62(1H，
t，J＝7.8Hz)，7.18(2H，t，J＝7.8Hz)，7.00～
7.08(3H，m)，6.86(1H，d，J＝7.8Hz)，6.78
(1H，dd，J＝4.9，7.8Hz)，5.44(1H，d，J＝5.
8Hz)，5.37(1H，brs)，5.23(1H，d，J＝5.
8Hz)，4.92(1H.brs)，4.02(2H，m)，3.76
(1H，m)，3.64(2H，m)，3.41(1H，m)
Embodiment 16
Compound shown in the formula (16)
4ml methyl alcohol is added in 24mg embodiment A gained compound and the 4-hydrazino-benzoic acid (Aldrich Chemical Co.), and mixture is heated and refluxed 2 hours, reaction soln with Sephadex LH-20 carry out column chromatography (1.8 * 44cm), use methanol-eluted fractions.The stream part that will contain desired product is concentrated into dried, the title compound shown in the 20.9mg formula (16), be the crystalline powder of redness.
Rf value: 0.31 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：655(M+H)
1H-NMR(500MHz.DMSO-d
6)，δ(ppm)：11.0
(1H，s)，10.5(1H，brs)，10.1(1H，brs)，9.
11(1H，s)，8.65(1H，d，J＝7.9Hz)，8.48(1H，
d，J＝7.9Hz)，7.80(2H，d，J＝8.3Hz)，7.18
(2H，t，J＝7.6Hz)，7.01～7.08(3H，m)，6.84
(2H，d，J＝8.3Hz)，5.20～5.60(3H，brs)，4.
96(1H，brs)，4.03(2H，m)，3.76(1H，m)，3.
65(2H，m)，3.41(1H，m)
Embodiment 17
Compound shown in the formula (17)
6ml 50% methyl alcohol joins in the compound and 38mg oxaminic acid hydrazine (oxamic hydrazine) (Aldrich Chemical Co.) of 26mg embodiment A gained, mixture was in 80 ℃ of heated and stirred 20 hours, reaction soln is concentrated into dried, add 15ml water and 50ml ethyl acetate, with 1N hydrochloric acid mixture being transferred to pH2 extracts, concentrate ethyl acetate layer, filter and collect the crystallization that settles out, get title compound shown in the 10mg formula (17).
Rf value: 0.38 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：606(M+H)
+
1H-NMR(500MHz.?DMSO-d
6).δ(ppm)：11.4
(1H，s)，11.0(1H，s)，10.4(1H，s)，10.0
(1H，s)，8.63(1H，d，J＝79Hz)，8.46(1H，d，
J＝7.9Hz)，8.38(1H，s)，8.11(1H，s)，7.21
(2H，t，J＝7.9Hz)，7.02～7.07(3H，m)，5.41
(1H，d，J＝5.8Hz)，5.35(1H，t，J＝5.8Hz)，5.
19(1H，d，J＝5.2Hz)，4.89(1H，d，J＝5.5Hz)，
4.03(2H，m)，3.76(1H，m)，3.63(2H，m)，3.
40(1H，m)
Embodiment 18
Compound shown in the formula (18)
26.7mg compound that embodiment 1 obtains and 5.5mg succinyl oxide are dissolved in the 0.5ml pyridine, stirred solution is 18 hours under room temperature, be concentrated into dried under the decompression, residue is dissolved in small amount of N, in the dinethylformamide, carry out high performance liquid chromatography (HPLC) [Chromatolex ODS, 20 * 250mm, mobile phase: 20% acetonitrile].Stream part the concentrating that will contain desired product removed acetonitrile, transfer to pH2 and use the 100ml ethyl acetate extraction, ethyl acetate layer is with anhydrous sodium sulfate dehydration and be concentrated into dried, residue is dissolved in the methyl alcohol, carries out column chromatography (internal diameter 1.5cm, long 90cm with Sephadex LH-20, use methanol-eluted fractions), the stream part that will contain desired product is concentrated into dried, title compound shown in the 9.7mg formula (18), be orange powder.
HPLC; Rt, 5.3 minutes (pillars: Chromatolex ODS; Interior diameter 4.6mm, long 250mm; Detect: UV305nm, velocity of flow: 1ml/ branch; Mobile phase 27.5% acetonitrile: trifluoroacetic acid=1000: 1)
FAB-MS(m/z)：657(M+Na)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：11.0
(1H，s)，10.7(1H，brs)，10.4(1H，brs)，10.
1(1H，brs)，8.64(1H，d，J＝7.9Hz)，8.47
(1H，d，J＝7.9Hz)，7.19(2H，t，J＝7.8Hz)，7.
01～7.07(3H，m)，5.42(2H，brs)，5.22(1H，
brs)，4.92(1H，brs)，4.02(2H，m)，3.75
(1H，m)，3.63(2H，m)，3.40(1H，m)，2.65
(2H，t，J＝7.3Hz)，2.52(2H，t，J＝7.3Hz)
Embodiment 19
Compound shown in the formula (19)
30mg embodiment 1 gained compound is dissolved in 0.5ml N, in the dinethylformamide, add the 0.1ml methyl-iodide, with mixture in stirring at room 18 hours, it is mixed with the 50ml ethyl acetate, mixture is continuously with 1% sodium bicarbonate aqueous solution and water washing, with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into dried, residue is dissolved in the methyl alcohol, (1.5 * 90cm) use methanol-eluted fractions to carry out column chromatography with Sephadex LH-20, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 18.0mg formula (19), be orange powder.
Rf value: 0.51 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF): acetate=20: 10: 10: 1)
FAB-MS(m/z)：563(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.9
(1H，s)，10.3(1H，s)，9.95(1H，s)，8.70
(1H，d，J＝8.3Hz)，8.53(1H，d，J＝8.3Hz)，7.
18(2H，t，J＝7.8Hz)，7.00～7.06(3H，m)，5.
41(1H，d，J＝5.4Hz)，5.34(1H，t，J＝5.4Hz)，
5.19(1H，d，J＝5.4Hz)，4.86(1H，d，J＝5.
4Hz)，4.02(2H，m)，3.75(1H，m)，3.62(2H，
m)，3.39(1H，m)，3.02(6H.s)
Embodiment 20
Compound shown in the formula (20)
82.1mg tertbutyloxycarbonyl (Boc) glycine is dissolved in the 1ml methylene dichloride, ice-cooled down with solution stirring 15 minutes, add the 96.7mg dicyclohexyl carbodiimide that is dissolved in the 1ml methylene dichloride, mixture was stirred 15 minutes down in ice-cooled, be dissolved in the compound that the 227.6mg embodiment 1 in the 6ml pyridine obtains toward wherein adding, mixture was stirred under room temperature 17 hours, reaction soln is concentrated into dried, residue is dissolved in the ethyl acetate, this solution is used saturated aqueous common salt continuously, sour water (pH2) and water washing, with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into driedly, residue carries out column chromatography (1.5 * 55cm with silica gel, eluent: toluene: methyl alcohol=6: 1), the stream part that will contain desired product concentrate as for, obtain the Boc derivative of the title compound shown in the 105.2mg formula (2), be orange powder.It is dissolved in the 1.2ml trifluoroacetic acid, under room temperature with solution stirring 30 minutes to remove tertbutyloxycarbonyl.Reaction soln is concentrated into dried, residue is dissolved in the 15ml water, and regulator solution is used n-butanol extraction to PH7.5-8, and 40mL water is added to (50ml) in the n-butanol layer, with dilute hydrochloric acid mixture is transferred to pH2, is concentrated into dried.Gained orange bag powder is dissolved in the methyl alcohol and carries out column chromatography (1.5 * 38cm use methanol-eluted fractions) with Sephadex LH-20, will contain stream part of desired product concentrated as for, must 63.7mg formula (20) shown in the hydrochloride of title compound, be orange powder.
HPLC; Rt, 8.7 minutes (pillars: Chromatolex ODS; Internal diameter, 4.6mm; Length 250mm; Detect UV, 305nm; Flow velocity 1ml/1 minute; Mobile phase, 20% acetonitrile: trifluoroacetic acid-1000: 1-→ 70% acetonitrile: trifluoroacetic acid=1000: 1; 30 minutes linear gradient elutions).
FAB-MS(m/z)：592(M+H)
+
1H-NMR(hydrochloride，400MHz，DMSO-d
6)，δ(ppm)：
11.3(1H，brs)，11.0(1H，brs)，10.5(1H，
s)，10.1(1H，s)，8.62(1H，d，J＝8.3Hz)，8.
46(1H，d，J＝8.3Hz)，8.31(2H，s)，7.19(2H，
t，J＝7.8Hz)，7.03～7.08(3H，m)，5.46(1H，
brs)，5.34(1H，brs)，5.27(1H，brs)，4.91
(1H，brd，J＝4.9Hz)，4.03(2H，m)，3.98(2H，
s)，3.76(1H，m)，3.64(2H，m)，3.40(1H，m)
Embodiment 21
Compound shown in the formula (21)
40.0mg embodiment A gained compound is dissolved in 3ml N, in the dinethylformamide, add 42.2mg l-deoxidation-l-diazanyl-D-sorb (sugar) alcohol, with the 0.1ml triethylamine, mixture heating up was refluxed 16 hours, be chilled to room temperature, carry out column chromatography (1.8 * 20cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 20.0mg formula (21).
FAB-MS(m/z)：699(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.91
(1H，s)，10.35(1H，brs)，9.96(1H，brs)，8.
73(1H，d，J＝8.9Hz)，8.54(1H，d，J＝8.9Hz)，
7.20(2H，t，J＝8.4Hz)，7.00-7.10(3H，m)，
5.76(1H，t，J＝3.8Hz)，5.42(1H，d，J＝5.
5Hz)，5.37(1H，brs)，5.22(1H，d，J＝5.
5Hz)，4.89(1H，brs)，4.67(1H，d，J＝3.
4Hz)，4.45(1H，d，J＝5.1Hz)，4.37(1H，d，J＝
7.0Hz)，4.25-4.43(2H，m)，4.00(2H，m)，3.
55-3.80(7H，m)，3.44-3.52(2H，m)，3.35-
3.44(2H，m)，3.05-3.20(2H.m)
Embodiment 22
Compound shown in the formula (22)
100mg embodiment A gained is dissolved in 5ml N at compound, in the dinethylformamide, adds the 100mg carbohydrazide, mixture is stirred 3 hours and was concentrated under 80 ℃ dried, and residue is dissolved in the methyl alcohol, removes insolubles with diatomite filtration.Concentrate gained filtrate, residue is dissolved in the small amount of methanol, with Sephadex LH-20 carry out column chromatography (1.5 * 20cm), use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in must 91.2mg formula (22).
Rf value: 0.1 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：593(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.96
(1H，s)，10.40(1H，s)，10.01(1H，s)，8.95
(1H，s)，8.65(1H，d，J＝8.2Hz)，8.50(1H，d，
J＝8.2Hz)，7.90(1H，s)，7.17(2H，t，J＝6.
9Hz)，7.00-7.10(3H，m)，5.43(1H，d，J＝4.
1Hz)，5.38(1H，brs)，5.20(1H，s)，4.90
(1H，s)，4.39(2H，brs)，4.04(2H，m)，3.75
(1H，m)，3.55-3.70(2H，m)，3.38(1H，m)
Embodiment 23
Compound shown in the formula (23)
15.0mg embodiment A gained compound is dissolved in 1ml N, in the dinethylformamide, add 32mg 3-hydroxybenzyl hydrazine dihydrochloride and 0.1ml 10% sodium bicarbonate aqueous solution, mixture stirred 4 hours down in 80 ℃, itself and 50ml ethyl acetate are mixed, use 0.2N hydrochloric acid continuously, the saturated brine purging compound, with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into dried, residue is dissolved in the small amount of methanol, with SephadexLH-20 carry out column chromatography (1.8 * 15cm), use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 15.3mg formula (23)
Rf value: 0.22 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=5: 1: 1)
FAB-MS(m/z)：641(M+H)
+
1H-NMR(200MHz，DMSO-d
6)，δ(ppm)：10.90
(1H，s)，10.38(1H，s)，9.99(1H，s)，9.30
(1H，s)，8.70(1H，d，J＝8.1Hz)，8.53(1H，d，
J＝8.5Hz)，6.86-7.22(8H，m)，6.61(1H，dd，
J＝2.2，8.4Hz)，6.03(1H，t，J＝5.1Hz)，5.43
(1H，d，J＝5.4Hz)，5.35(1H，t，J＝5.0Hz)，5.
22(1H，d，J＝5.4Hz)，4.89(1H，d，J＝5.4Hz)，
4.19(2H，d，J＝5.1Hz)，4.00(2H，m)，3.72
(1H，m)，3.53-3.70(2H，m)，3.38(1H，m)
Embodiment 24
Compound shown in the formula (24)
64.6mg the compound of embodiment A gained is dissolved in 2ml N, in the dinethylformamide, adds 30mg 2-cyanoethyl hydrazine, stirs the mixture 1.5 hours in 90 ℃.In reaction soln, add 50ml 0.2N hydrochloric acid, with ethyl acetate (50ml * 2) extraction mixture, ethyl acetate layer is concentrated into dried, residue is dissolved in the small amount of methanol, carry out column chromatography (1.8 * 30cm) with Sephadex LH-20, use methanol-eluted fractions, concentrate the stream part that contains desired product and extremely do, get the title compound shown in the 45.0mg formula (24).
Rf value: 0.39 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=3: 1)
FAB-MS(m/z)：588(M+H)
+
1H-NMR(200MHz.DMSO-d
6)，δ(ppm)：10.91
(1H，s)，10.36(1H，s)，9.98(1H，s)，8.70
(1H，d，J＝8.4Hz)，8.53(1H，d，J＝8.4Hz)，7.
18(2H，t，J＝8.4Hz)，6.95-7.10(3H，m)，6.
15(1H，t，J＝4.2Hz)，5.42(1，d，J＝5.7Hz)，
5.34(1H.brs).5.23(1H，d，J＝4.4Hz)，4.91
(1H，d，J＝5.3Hz)，4.00(2H，m)，3.72(1H，
m)，3.55-3.70(2H，m)，3.39(1H，m)，3.30
(2H，td，J＝4.2，6.2Hz)，2.69(2H，t.J＝6.
2Hz)
Embodiment 25
Compound shown in the formula (25)
1.09g embodiment A gained compound is dissolved in 35ml N, in dinethylformamide-2ml water, adds 455mg 2-diazanyl-2-tetrahydroglyoxaline hydrobromide and 211mg sodium bicarbonate.Mixture stirred 2 hours and was concentrated into dried in 80 ℃, residue is dissolved in the 300ml0.2N hydrochloric acid and uses n-butanol extraction (1L * 2).N-butanol layer is concentrated into dried, residue is dissolved in the small amount of methanol, with Sephadex LH-20 carry out column chromatography (3.0 * 80cm) use methanol-eluted fractions, and the component that will contain desired product is concentrated into dried, the title compound shown in the 650mg formula (25).
Rf value: 0.55 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, propyl carbinol: acetate: water=4: 1: 1)
FAB-MS(m/z)：603(M+H)
+
1H-NMR(400MHz.DMSO-d
6)，δ(ppm)：11.2
(1H，s)，10.90(1H，brs)，10.50(1H，s)，10.
14(1H，s)，9.42(1H，brs)，8.92(1H，brs)，
8.62(1H，d，J＝10.6Hz)，8.45(1H，d，J＝9.
5Hz)，7.22(2H，t，J＝6.5Hz)，7.02-7.10
(3H，m)，5.48(1H，d，J＝4.7Hz)，5.32(2H，
brm)，4.94(1H，d，J＝3.5Hz)，4.04(2H，m)，
3.70-3.90(5H，m)，3.54-3.70(2H，m)，3.41
(1H，m)
Embodiment 26
Compound shown in the formula (26)
48.3mg the compound of embodiment A gained is dissolved in 1ml N, in the dinethylformamide, adds 14.3mg 1-amino-4-(2-hydroxyethyl) piperazine and 0.1ml saturated sodium bicarbonate aqueous solution, stirs the mixture 2 hours in 80 ℃.It is distributed between 50ml ethyl acetate and 50ml water, in water layer, add 5ml 0.2N hydrochloric acid, with n-butanol extraction mixture (100ml * 2), n-butanol layer is concentrated into dried, residue is dissolved in the small amount of methanol, with Sephadex LH-20 carry out column chromatography (1.8 * 30cm), use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 22mg formula (26).
Rf value: 0.53 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, propyl carbinol: acetate: water=4: 1: 1)
FAB-MS(m/z)：648(M+H)
+
1H-NMR(400MHz.DMSO-d
6)，δ(ppm)：10.92
(1H，s)，10.50(2H，brs)，10.10(1H，s)，8.
66(1H，d，J＝7.2Hz)，8.50(1H，d，J＝8.9Hz)，
7.18(2H，t，J＝8.9Hz)，7.02-7.12(3H，m)，
5.46(1H，d，J＝5.6Hz)，5.25-5.40(3H，
brm)，4.86(1H，d，J＝5.6Hz)，3.95-4.20
(4H，m)，3.70-3.90(4H，m)，3.55-3.70(4H，
m)，3.20-3.50(6H，m)
Embodiment 27
Compound shown in the formula (27)
24mg embodiment A gained compound is dissolved in 0.6ml N, in the dinethylformamide, adds 10mg tertiary butyl kappa acid esters (t-butyl Carbazinate acid).Stirred the mixture 6 hours in 80 ℃.Mix with the 50ml ethyl acetate, continuous water of mixture (30ml * 2) and saturated brine washing, with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into dried, residue is dissolved in the 1ml methyl alcohol, carry out column chromatography (1.6 * 20cm) with Sephadex LH-20, use methanol-eluted fractions, concentrate the stream part of closing desired product and extremely do, get title compound shown in the 27.2mg formula (27).
Rf value: 0.42 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co); Developping agent, chloroform: methyl alcohol=4: 1)
FAB-MS(m/z)：634(M+H)
+
1H-NMR(400MHz.DMSO-d
6)，δ(ppm)：10.99
(1H，s)，10.42(1H，s)，10.02(1H，s)，9.82
(1H，brs)，8.65(1H，d，J＝7.7Hz)，8.49.(1H，
d，J＝7.7Hz)，7.18(2H，t，J＝7.7Hz)，7.00-
7.10(3H，m)，5.42(1H，brs)，5.35(1H，
brs)，5.21(1H，brs)，4.90(1H，brs)，4.02
(2H，m)，3.72(1H，m)，3.56-3.70(2H，m)，3.
40(1H，m)，1.50(9H.s)
Embodiment 28
Compound shown in formula (28) and the formula (29)
177mg embodiment 1 gained compound is dissolved in 6ml N, in the dinethylformamide, adds the 0.68ml allyl bromide 98.Stirred the mixture under the room temperature 1 day, and in mixture, added 200ml water, with ethyl acetate (200ml * 3) extraction mixture, with saturated brine make ethyl acetate layer dehydration and concentrate as for.Residue is dissolved in the 3ml methyl alcohol, with Sephadex LH-20 carry out column chromatography (2.5 * 40cm), use methanol-eluted fractions.The stream part that will contain desired product respectively is concentrated into dried, the title compound shown in the 42.1mg formula (28) and the title compound shown in the 67.5mg formula (29).Compound shown in the formula (28):
Rf value: 0.68 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=2: 1)
FAB-MS(m/z)：575(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)10.90
(1H，s)，10.38(1H，s)，9.98(1H，s)，8.70
(1H，d，J＝9.0Hz)，8.52(1H，d，J＝10.2Hz)，
7.20(2H，t，J＝7.7Hz)，6.95-7.08(3H，m)，
5.92(2H，m)，5.40(1H，d，J＝6.4Hz)，5.32
(1H，m)，5.20(2H，m)，5.05(1H，d，J＝11.
5Hz)，4.88(1H，d，J＝5.8Hz)，4.00(2H，m)，
3.67-3.78(3H，m)，3.58-3.65(2H，m)，3.35
(1H, m) compound shown in the formula (29):
Rf value: 0.75 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=2: 1)
1H-NMR(400MHz.DMSO-d
6).δ(ppm)：10.91
(1H，s)，10.40(1H，brs)，10.00(1H，brs).
8.66(1H，d，J＝9.4Hz)，8.50(1H，d，J＝9.
4Hz)，7.18(2H，t，J＝8.0Hz)，7.00-7.10
(3H，m)，5.90(2H，ddt，J＝6.3，10.2，17.
0Hz)，5.42(1H，d，J＝5.3Hz)，5.33(1H，
brs)，5.23(2H，d，J＝17.0Hz)，5.22(1H，
brs)，5.04(2H，d，J＝10.2Hz)，4.91(1H，
brs)，4.02(2H，m)，3.97(4H，d，J＝6.3Hz)，
3.70(1H，m)，3.51-3.66(2H.m)，3.35(1H.
m)
Embodiment 29
Compound shown in formula (30) and the formula (31)
The compound that 20mg embodiment 1 obtains is dissolved in 1ml N, in the dinethylformamide, adds the 0.3ml bromotoluene, the mixture stirring is spent the night, mix with the 40ml ethyl acetate, water (30ml * 2) and saturated brine continuous washing mixture are with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into dried.Residue is dissolved in the 1ml methyl alcohol, with SephadexLH-20 carry out column chromatography (1.6 * 30cm), use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried respectively, the compound shown in the 13.2mg formula (30) and the compound shown in the 7.2mg formula (31).The compound that formula (30) is shown:
Rf value: 0.44 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=3: 1)
FAB-MS(m/z)：715(M+H)
+
1H-NMR(200MHz.DMSO-d
6)，δ(ppm)：10.85
(1H，s)，10.35(1H，s)，9.96(1H，s)，8.65
(1H，d，J＝8.5Hz)，8.45(1H，d，J＝9.0Hz)，7.
50-7.65(4H，m)，7.10-7.40(8H，m)，6.95-
7.10(3H，m)，5.40(1H，d，J＝5.4Hz)，5.30
(1H，brs)，5.18(1H，d，J＝4.9Hz)，4.83(1H，
d，J＝4.9Hz)，4.58(2H，s)，4.55(2H，s)，4.
00 (2H, m), 3.46-3.80 (3H, m), 3.36 (1H, m) compound shown in the formula (31):
Rf value: 0.38 (silica gel 60F
254(Kiesel gel 60F
254, MerckCo.); Developping agent, chloroform: methyl alcohol=3: 1)
FAB-MS(m/z)：625(M+H)
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)：10.88
(1H，s)，10，40(1H，brs)，10.00(1H，brs)，
8.67(1H，d，J＝7.9Hz)，8.51(1H，d，J＝7.
3Hz)，7.50(2H，d，J＝6.9Hz)，7.30(2H，t，J＝
6.9Hz)，7.21(1H，t，J＝6.9Hz)，7.16(2H，t，
J＝7.3Hz)，6.96-7.07(3H，m)，6.13(1H，t，J
＝5.3Hz)，5.42(1H，d，J＝5.9Hz)，5.21(1H，
d.J＝5.3Hz)，4.91(1H，brs)，4.55(1H，
brs)，4.28(2H，d，J＝5.3Hz)，4.02(2H，m)，
3.72(1H，m)，3.55-3.70(2H，m)，3.40(1H.
m)
Embodiment 30
Compound shown in the formula (32)
1.4g the compound that embodiment A obtains is dissolved in 30ml N, in the dinethylformamide, add 1g carbazic acid methyl esters (methyl carbazinate), stirred the mixture 2 hours in 80 ℃, in mixture, add 400ml, with ethyl acetate (500ml * 3) extraction mixture, with the gained ethyl acetate layer concentrate as for, residue is dissolved in the 5ml methyl alcohol, with Sephadex LH-20 carry out column chromatography (3.0 * 80cm), use methanol-eluted fractions.The stream part that will contain desired product is concentrated into dried, the title compound shown in the 1.3g formula (32).
Rf value: 0.18 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=4: 1)
FAB-MS(m/z)：592(M+H)
+
1H-NMR(300Mz，DMSO-d
6)，δ(ppm)：11.00
(1H，s)，10.42(1H，brs)，10.18(1H，s)，10.
04(1H，brs)，8.64(1H，d，J＝7.6Hz)，8.47
(1H，d，J＝8.3Hz)，7.20(2H，t，J＝8.3Hz)，7.
00-7.10(3H，m)，5.42(1H，brs)，5.35(1H，
brs)，5.21(1H，brs)，4.91(11，brs)，4.02
(2H，m)，3.75(3H，s)，3.50-3.70(3H，m)，3.
40(1H.m)
Embodiment 31
Compound shown in the formula (33)
The compound that the 90mg embodiment A obtains is dissolved in 1ml N, dinethylformamide, 67mg (2R, 3s)-3,4-O-isopropylidene-2,3, in the 4-trihydroxybutane carbohydrazide, mixture was stirred 7 hours in 80 ℃, again in stirring at room 3 days, in mixture, add 50ml water, with ethyl acetate (50ml * 2) extraction, the gained ethyl acetate layer is concentrated into dried, residue is dissolved in the 3ml methyl alcohol, with SephadexLH-20 carry out column chromatography (1.8 * 25cm), use methanol-eluted fractions.To contain desired product stream part be concentrated into dried, title compound shown in the 112mg formula (33).
Rf value: 0.14 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=4: 1)
FAB-MS(m/z)：692(M+H)
+
1H-NMR(300MHz.DMSO-d
6)，δ(ppm)：11.01
(1H，s)，10.70(1H，s)，10.45(1H，s)，10.05
(1H，s)，8.75(1H，d，J＝7.4Hz)，8.47(1H，d，
J＝7.4Hz)，7.21(2H，t，J＝7.4Hz)，7.00-7.
10(3H，m)，6.26(1H，d，J＝6.7Hz)，5.44(1H，
d，J＝5.9Hz)，5.39(1H，brs)，5.24(1H，d，J＝
5.9Hz)，4.93(1H，d，J＝5.9Hz)，4.31(1H，
dd，J＝6.7，11.9Hz)，4.22(1H，t，J＝6.7Hz)，
4.10(1H，ddd，J＝6.7，6.7，11.9Hz)，4.05
(2H，m)，3.91(1H，t，J＝6.7Hz)，3.76(1H，
m)，3.57-3.71(2H，m)，3.40(1H，m)，1.45
(3H，s)，1.36(3H，s)
Embodiment 32
Compound shown in the formula (34)
25mg embodiment 1 gained compound is dissolved in the 5ml anhydrous tetrahydro furan, add 10mg tosic acid acid anhydride, stirring at room mixture one day, reaction soln is concentrated into dried, residue is dissolved in the 1ml methyl alcohol, with Sephadex LH-20 carry out column chromatography (1.8 * 20cm), use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 12.3mg formula (34).
Rf value: 0.49 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=3: 1: 1)
FAB-MS(m/z)：688(M+H)
+
1H-NMR(300MHz.DMSO-d
6)，δ(ppm)：10.98
(1H，s)，10.87(1H，s)，10.42(1H，s)，10.05
(1H，s)，8.54(1H，d，J＝7.9Hz)，8.38(1H，d，
J＝7.9Hz)，7.84(2H，d，J＝8.7Hz)，7.44(2H，
d，J＝8.7Hz)，7.19(2H，t，J＝7.9Hz)，7.00-
7.08(3H，m)，5.43(1H，d，J＝4.7Hz)，5.35
(1H，brs)，5.23(1H，d，J＝4.9Hz)，4.90(1H，
d，J＝4.4Hz)，4.04(2H，m)，3.75(1H，m)，3.
55-3.70(2H，m)，3.40(1H，m)，2.42(3H，s)
Embodiment 33
Compound shown in the formula (35)
The compound that 20mg embodiment 1 obtains is dissolved in the 2ml tetrahydrofuran (THF), add the 0.1ml phenylcarbimide, under room temperature, stirred the mixture 2 hours, with reaction soln concentrate as for, residue is dissolved in the 1ml methyl alcohol, with Sephodex LH-20 carry out column chromatography (1.6 * 30cm), use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, the title compound shown in the 12mg formula (35).
Rf value: 0.38 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：653(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：11.00
(1H，s)，10.40(1H，brs)，10.10(1H，brs)，
9.48(1H，s)，9.50(1H，s)，8.67(1H，d，J＝8.
3Hz)，8.50(1H，d，J＝8.3Hz)，7.48(2H，d，J＝
7.8Hz)，7.27(2H，t，J＝7.8Hz)，7.20(2H，t，
J＝7.8Hz)，6.95-7.10(4H，m)，5.43(1H，d，J
＝4.2Hz)，5.30(1H，brs)，5.23(1H，brs)，4.
95(1H，brs)，4.03(2H，m)，3.75(1H，m)，3.
58-3.70(2H，m)，3.38(1H，m)
Embodiment 34
Compound shown in the formula (36)
The compound that 15mg embodiment 1 obtains is dissolved in the 2ml tetrahydrofuran (THF), add 16 μ l Benzoyl chlorides, stirred the mixture under the room temperature 2 hours, distillation removes and desolvates, residue is dissolved in the 1ml methyl alcohol, with Sephaedx LH-20 carry out column chromatography (1.6 * 20cm), use methanol-eluted fractions, the stream part that will contain desired product concentrates, and gets the title compound shown in the 12mg formula (36).
Rf value: 0.57 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：639(M+H)
+
1H-NMR(200MHz，DMSO-d
6)，δ(ppm)：11.35
(1H，brs)，11.04(1H，s)，10.45(1H，brs)，
10.08(1H，brs)，8.66(1H，d，J＝8Hz)，8.49
(1H，d，J＝8.5Hz)，8.04(2H，d，J＝7.1Hz)，7.
55-7.78(3H，m)，7.20(2H，t，J＝8.5Hz)，7.
00-7.15(3H，m)，5.45(2H，brs)，5.25(1H，
brs)，4.97(1H，brs)，4.02(2H，m)，3.55-3.
82(3H，m)，3.41(1H，m)
Embodiment 35
Compound shown in the formula (37)
The compound that the 25mg embodiment A obtains is dissolved in 1.5ml N, in the dinethylformamide, (α-picolinohydrazide), mixture stirred 2 hours down in 80 ℃, mixed with the 50ml ethyl acetate again to add 30mg α-pyridine formyl hydrazine, water and saturated brine are washed mixture continuously, use anhydrous sodium sulfate drying, be concentrated into driedly, residue is dissolved among the 1ml methyl alcohol, with Sephadex LH-20 carry out column chromatography (1.8 * 15cm), use methanol-eluted fractions.The stream part that contains desired product is concentrated into dried, the title compound shown in the 30mg formula (37).
Rf value: 0.58 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：640(M+H)
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)：11.43
(1H，s)，11.02(1H，s)，10.45(1H，s)，10.07
(1H，s)，8.82(1H，d，J＝4.2Hz)，8.75(1H，d，
J＝7.3Hz)，8.48(1H，d，J＝7.8Hz).8.12(2H，
m)，7.75(1H，m)，7.20(2H，t，J＝7.0Hz)，7.
00-7.15(3H，m)，5.45(1H，d，J＝6.3Hz)，5
40(1H，brs)，5.25(1H.d，J＝6.3Hz)，4.96
(1H，brs)，4.04(2H，m)，3.76(1H，m)，3.55-
3.72(2H，m)，3.42(1H.m)
Embodiment 36
Compound shown in the formula (38)
The compound that the 30mg embodiment A obtains is dissolved in 1ml N, in the dinethylformamide, adds 30mg 2-hydrazinoethanol, stirred the mixture 2 hours in 80 ℃, be concentrated into driedly, residue is dissolved in the 1ml methyl alcohol, with Sephadex LH-20 carry out column chromatography (1.8 * 20cm), use methanol-eluted fractions.The stream part that contains desired product is concentrated into dried, the title compound shown in the 32mg formula (38).
Rf value: 0.32 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=2: 1)
1H?NMR(300MHz，DMSO-d
6)，δ(ppm)：10.91
(1H，s)，10.35(1H，brs)，9.98(1H，brs)，8.
70(1H，d，J＝6.7Hz)，8.53(1H，d，J＝6.9Hz)，
7.18(2H，t，J＝7.6Hz)，6.99-7.06(3H，rm)，
5.76(1H，t，J＝5.2Hz)，S.41(1H，d，J＝5.
6Hz)，5.32(1H，brs)，5.20(1H，d，J＝5.
2Hz)，4.90(1H，brs)，4.51(1H，t，J＝4.
9Hz)，3.96-4.06(2H，m)，3.73(1H，m)，3.55
-3.70(4H，m)，3.39(1H，m)，3.12(2H，m)
Embodiment 37
Compound shown in the formula (39)
The compound that the 40mg embodiment A obtains is dissolved in 2ml N, in the dinethylformamide, adds 10mg 1-amino-pyrrolidine hydrochloride and 0.1ml sodium bicarbonate aqueous solution.Under 80 ℃ mixture was stirred 2 hours, add 40ml water, mixture extracts with ethyl acetate (40ml * 2), with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into driedly, residue is dissolved in the 1ml methyl alcohol, carries out column chromatography (1.8 * 20cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, 10.0mg, the title compound shown in the formula (39).
Rf value: 0.33 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=4: 1)
FAB-MS(m/z)：589(M+H)
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)：10.91
(1H，s)，10.35(1H，s)，9.95(1H，s)，8.78
(1H，d，J＝8.3Hz)，8.52(1H，d，J＝8.3Hz)，7.
16(2H，t，J＝7.6Hz)，6.98-7.06(3H，m)，5.
40(1H，d，J＝5.5Hz)，5.33(1H，t，J＝5.7Hz)，
5.18(1H，d，J＝5.5Hz)，4.85(1H，d，J＝4.
8Hz)，4.02(2H，m)，3.74(1H，m)，3.53-3.68
(2H，m)，3.30-3.42(5H，m)，1.97(4H，m)
Embodiment 38
Compound shown in the formula (40)
90mg 6-benzyloxymethyl-1,11-two benzyloxies-12,13-dehydrogenation-5H-indoles also (2,3-a) pyrrolo-(3,4-c) carbazole-4,7 (6H)-diketone (the disclosed compound of PCT/WO91/18003), 1.3g silver suboxide and 550mg 4_ molecular sieve are suspended in the 30ml dry-out benzene.After the reflux 20 minutes, the past 416.4mg α-bromo-3-deoxidation-3-azido--2,4, the 6-triacetyl-solution of D-glucose in the 5ml dry-out benzene of wherein dripping in 10 minutes.Reflux 2 days, use the diatomite filtration insolubles, filtrate is concentrated into dried, residue is dissolved in the 150ml ethyl acetate, use 0.2N hydrochloric acid, water and saturated brine continuous washing are used anhydrous sodium sulfate drying, are concentrated into dried, residue is dissolved in the 5ml chloroform, (3.0 * 80cm), the stream part that will contain desired product with the chloroform wash-out is concentrated into dried, and residue is with the preparation thin layer chromatography (normal hexane: acetone: tetrahydrofuran (THF)=3: 1: 01 (Rf: 0.5) of purifying to carry out column chromatography with Sephadex LH-20, then, toluene: acetone=10: 1 (Rf: 0.5)) obtains 9.2mg 6-benzyloxymethyl-1,11-benzyloxy-12,13-dehydrogenation-13-(β-D-glucopyranosyl)-5H-indoles also (2,3-a) pyrrolo-(3,4-c) carbazoles-5,7 (6H)-diketone.
9.2mg the gained compound is dissolved in the single hydrazine hydrate of 1ml, solution was stirred under room temperature 4 hours, mix with the 30ml ethyl acetate, use 0.2N hydrochloric acid, water and saturated brine continuous washing mixture, use anhydrous sodium sulfate drying, be concentrated into dried, residue is dissolved in 0.5ml tetrahydrofuran (THF)-1ml methyl alcohol, adds palladium black, stirs the mixture in the room temperature hydrogen stream 3 hours, use the diatomite filtration insolubles, add 1.5ml 10% hydrochloric acid-methyl alcohol in filtrate, mixture is concentrated into dried, residue is dissolved in the 0.5ml methyl alcohol, carry out column chromatography (1.0 * 15cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, the title compound shown in the 2.0mg formula (40).
Rf value: 0.5 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, propyl carbinol: acetate: water=4: 1: 1)
FAB-MS(m/z)：534(M+H)
+
1H-NMR(400Hz，DMSO-d
6)，δ(ppm)：10.80
(1H，s)，10.4(1H，s).10.20(1H，s)，8.79
(1H，d，J＝7.9Hz)，8.52(3H，br)，8.50(1H，
d，J＝9.2Hz)，7.61(1H，d，J＝6.6Hz)，7.16
(1H，dd，J＝9.2，9.2Hz)，7.10(1H，dd，J＝9.
2，9.2Hz)，7.05(1H，dd，J＝9.2，9.2Hz)，7.
00(1H，dd，J＝9.2，9.2Hz)，6.42(1H，d，J＝5.
2Hz)，6.16(1H，d，J＝3.9Hz)，5.18(1H，br)，
4.93(1H，br)，4.40(1H，m)，4.16(1H，m)，4.
03(1H，m)，3.78(1H，m)，3.68(1H，m)，3.42
(1H，m)
Embodiment 39
Compound shown in the formula (41)
The resulting compound of 30mg embodiment A is dissolved in 1.5ml N; in the dinethylformamide; add 60mg cyano group ethanoyl hydrazine; mixture stirred 9 hours in 80 ℃; it is mixed with the 30ml ethyl acetate; the washing of the continuous water of mixture and saturated brine is with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into dried.Residue is dissolved in the small amount of methanol, with Shephadex LH-20 carry out column chromatography (1.5 * 15cm), use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, the title compound shown in the 27.8mg formula (41).
Rf value: 0.53 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=3: 1: 0.1)
FAB-MS(m/z)：601(M+H)
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)：11.14
(1H，s)，11.01(1H，s)，10.42(1H，s)，10.04
(1H，s)，8.65(1H，d，J＝7.6Hz)，8.47(1H，d，
J＝7.6Hz)，7.21(2H，t，J＝7.6Hz)，7.05(3H，
t，J＝7.6Hz)，5.41(2H，d，J＝4.5Hz)，5.19
(1H，d，J＝6.8Hz)，4.90(1H，d，J＝6.8Hz)，4.
13(2H，s)，4.04(2H，br)，3.75(1H，m)，3.64
(2H，m)，3.43(1H.m)
Embodiment 40
Compound shown in the formula (42)
1g12,13,-dihydro-1,11-dihydroxyl-13-(β-D-glucopyranosyl)-5H-indoles also (2,3-a) pyrrolo-(3,4-c) carbazole-5,7 (6H)-diketone is dissolved in the 25ml tetrahydrofuran (THF), adds the diethyl ether solution of excessive diazomethane, stir the mixture in 4 ℃ and to spend the night, the yellow mercury oxide that filter to collect forms is dissolved in it in single hydrazine hydrate of 3ml, makes this solution in room temperature reaction 1.5 hours, add the 200ml pure water after the reaction, filter and collect the gained precipitation, use pure water and methanol wash continuously, drying under reduced pressure obtains the title compound shown in the 683.4mg formula (42).
HPLC; Rt:10.5 minute (pillar: Chromatolex ODS; Internal diameter 4.6mm; Long, 250mm; Detect UV305nm, flow velocity 1ml/ minute, mobile phase: methyl alcohol: water=6: 4).
FAB-MS(m/z)：563(M+H)
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)：10.9
(1H，s)，8.87(1H，d，J＝7.8Hz)，8.65(1H，d，
J＝7.8Hz)，7.35(1H，t，J＝7.8Hz)，7.23(1H，
t，J＝7.8Hz)，7.25(1H，d，J＝7.8Hz)，7.18
(1H，d，J＝7.8Hz)，6.90(1H，d，J＝9.3H)，5.
40(1H，br.s)，5.18(1H，brs)，5.00(2H，
brs)，4.90(2H，brs)，4.06(6H，s)，4.00
(2H，m)，3.78(1H，m)，3.63(2H，m)，3.42
(1H，m)
Embodiment 41
Compound shown in the formula (43)
According to the method for embodiment 2, the compound that obtains from 679mg embodiment 40 makes the title compound shown in the 708.8mg formula (43).
HPLC; Rt:10.9 minute (pillar: Chromatolex ODS; Internal diameter 4.6mm; Long, 250mm; Detect UV310nm, flow velocity 1ml/ minute, mobile phase: acetonitrile: water=2.8-→ acetonitrile: water=6: 4,30 minutes linear gradient elutions)
FAB-MS(m/z)：618[M]
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：13.5
(1H，brs)，11.1(1H，s)，9.01(1H，s)，8.83
(1H，d，J＝7.8Hz)，8.63(1H，d，J＝7.8Hz)，7.
39(1H，t，J＝7.8Hz)，7.37(1H，t，J＝7.8Hz)，
7.29(1H，d，J＝7.8Hz)，7.22(1H，d，J＝7.
8Hz)，6.94(1H，d，J＝9.3Hz)，5.43(1H，d，J＝
5.4Hz)，5.22(1H，d，J＝5.4Hz)，5.01(1H，
brs)，4.93(1H，d，J＝5.4Hz)，4.07(6H，s)，
4.05(1H，m)，3.96(1H，m)，3.79(1H，m)，3.
60(2H，m)，3.44(1H，m)
Embodiment 42
Compound shown in the formula (44)
The compound that 704mg embodiment 41 obtains is dissolved in 10ml N, in the dinethylformamide, palladium/the carbon (Pd-C) that adds 60mg 10%, room temperature and stirring are down with mixture hydrogenation 6 hours, remove Pd-C with the filter paper filtering reaction mixture on the diatom of shop, add the 200ml ethyl acetate in filtrate, mixture extracts with 50ml sodium bicarbonate aqueous solution (pH8).Water layer transfers to pH2, uses ethyl acetate (500ml) extraction again.Ethyl acetate layer concentrates 2% sodium bicarbonate aqueous solution layer down and is adsorbed in (internal diameter 3cm, long 30cm) on the Diaion HP20 post with 2% sodium bicarbonate aqueous solution (70ml) extraction, decompression, washes with water, uses the 300ml methanol-eluted fractions again.Meoh eluate is concentrated into dried, residue liquid is in small amount of N, and in the dinethylformamide, solution is with preparation HPLC chromatography (pillar: Chromatolex ODS; Internal diameter 20mm; Long, 250mm; Detect UV310nm; Flow velocity 9ml/ minute; Mobile phase: acetonitrile: water=25: 75).The stream part that will contain desired product is concentrated into dried, and residue is dissolved in the less water, carries out column chromatography (internal diameter 3cm, long 63cm), water: methyl alcohol=9: 1 wash-outs with SephadexG-15.The stream part that will contain desired product concentrates and lyophilize, gets the sodium salt of title compound shown in the 84.2mg formula (44).
HPLC:Rt8.9 minute (pillar: Chromatolex ODS; Internal diameter 4.6mm; Long, 250mm; Detect UV310nm; Flow velocity 1ml/ branch; Mobile phase, acetonitrile: water: trifluoroacetic acid=300: 700: 1)
FAB-MS(m/z)：643(M+Na)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.9
(1H，brs)，8.85(1H，d，J＝7.8Hz)，8.63(1H，
d，J＝7.8Hz)，7.33(1H，t，J＝7.8Hz)，7，31
(1H，t，J＝7.8Hz)，7.24(1H，d，J＝7.8Hz)，7.
16(1H，d，J＝7.8Hz)，6.89(1H，d，J＝9.3Hz)，
5.63(1H，brs)，5.42(1H，brs)，5.10(1H，
brs)，4.99(1H，brs)，4.06(6H，s)，4.02
(2H，m)，3.80(1H，m)，3.67(1H，t，J＝8.
8Hz)，3.58(1H，m)，3.42(1H，t，J＝8.3Hz)，
3.34(2H，s)
Embodiment 43
According to the method identical with embodiment 2, the compound that obtains from 70mg embodiment 4 makes the title compound shown in the 23.8mg formula (45).
FAB-MS(m/z)：641(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.8
(1H，s)，9.26(1H，d，J＝7.8Hz)，9.09(1H，d，
J＝7.8Hz)，8.94(1H，s)，7.78(1H，d，J＝7.
8Hz)，7.74(1H，d，J＝7.8Hz)，7.50(2H，t，J＝
7.8Hz)，6.98(1H，d，J＝9.3Hz)，5.44(1H，d，
J＝5.9Hz)，5.33(1H，brs)，5.09(1H，d，J＝5.
4Hz)，3.96(2H，m)，3.85(1H，m)，3.67(2H，
m)，3.59(3H，s)，3.5?6(1H，m)
Embodiment 44
Compound shown in the formula (46)
According to the method identical with embodiment 42, the compound that obtains from 1g embodiment 43 makes the title compound shown in the 210mg formula (46)
FAB-MS(m/z)：643(M+H)
+
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：10.7
(1H，s)，9.26(1H，d，J＝7.8Hz)，9.09(1H，d，
J＝7.8Hz)，7.74(1H，d，J＝7.8Hz)，7.71(1H，
d，J＝7.8Hz)，7.46(2H，t，J＝7.8Hz)，6.93
(1H，d，J＝9.2Hz)，6.00(1H，brs)，5.42(1H，
brs)，5.31(1H，brs)，5.03(1H，brs)，3.96
(2H，brs)，3.85(2H，s)，3.83(1H，m)，3.59
(3H，s)，3.50-3.70(3H，m)
Embodiment 45
Compound shown in the formula (47)
According to the method identical with embodiment 5, the compound that obtains from 51.4mg embodiment 4 makes the title compound shown in the 48.2mg formula (47).
FAB-MS(m/z)：613(M+H)
+
1H-NMR(400MHz，DMSO-d
6)，δ(ppm)：10.9
(1H，brs)，10.8(1H，brs).9.20(1H，m)，9.
03(1H，m)，8.48(1H，s)，7.75(1H，d，J＝7.
8Hz)，7.70(1H，d，J＝7.8Hz)，7.45(2H，t，J＝
7.8Hz)，6.93(1H，brt，J＝9.3Hz)，5.41(2H，
m)，5.04(1H，d，J＝5.9Hz)，3.99(2H，brs)，
3.86(1H，m)，3.60(3H，s)，3.52-3.67(3H，
m)
Embodiment 46
Compound shown in the formula (48)
According to the method identical with embodiment 6, the compound that obtains from 14.1mg embodiment 4 makes the title compound shown in the 13mg formula (48).
FAB-MS(m/z)：627(M+H)
+
1H-NMR(500MHz，DMSO-d
6)，δ(ppm)：10.8(2H，s)，9.20(1H，m)，9.04(1H，m)，7.74(2H，m)，7.47(2H，m)，6.93(1H，m)，5.41(1H，m)，5.32(1H，brs)，5.04(1H，m)，3.96(2H，brs)，3.85(1H，m)，3.58(3H，s)，3.50-3.70(3H，m)，2.12(3H，s)
Embodiment 47
Compound shown in the formula (49)
The single hydrazine hydrate of 1ml is added to 3.2mg12,13-dihydro-2,10-dihydroxyl-13-(β-D-glucopyranosyl)-5H-indoles also (2,3-a) pyrrolo-(3,4-c) carbazole-5, in 7 (6H)-diketone, in stirring at room mixture 2 hours, it is distributed between ethyl acetate and 0.2N hydrochloric acid, continuously water and saturated salt washing ethyl acetate layer, be concentrated into dried, residue is dissolved in the small amount of methanol, with Sephadex LH-20 carry out column chromatography (1.0 * 5cm), use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, the title compound shown in the 3.0mg formula (49).
Rf value: 0.22 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=3: 1: 1)
FAB-MS(m/z)：534[M]
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)，11.16
(1H，s)，9.76(1H，s)，9.73(1H，s)，8.90
(1H，d，J＝7.3Hz)，8.82(1H，d，J＝7.3Hz)，7.
18(1H，d，J＝2.0Hz)，6.9?8(1H，d，J＝2.0Hz)，
6.83(2H，dt，J＝2.0，7.3Hz)，5.97(1H，d，J＝
7.2Hz)，5.84(1H，t，J＝3.3Hz)，5.32(1H，d，
J＝5.3Hz)，5.10(1H，d，J＝5.3Hz)，4.93(1H，
d，J＝5.2Hz)，4.90(2H，s)，4.04-3.86(2H，
m)，3.78(1H，m).3.60-3.35(3H，m)
Embodiment 48
Compound shown in the formula (50)
0.4ml hydrazine hydrate is added to 7.1mg 2,10-two fluoro-12,13-dihydro-13-(β-D-glucopyranosyl)-5H-indoles were also in (2,3-a) pyrrolo-(3,4-c) carbazoles-5,7 (6H)-diketone, in stirring at room mixture 40 minutes.Toward wherein adding the 1.34ml concentrated hydrochloric acid, use ethyl acetate extraction, wash ethyl acetate layer and concentrated with water, residue is dissolved in 3.7ml N, in dinethylformamide and the 0.37ml concentrated hydrochloric acid, spend the night, it is distributed between ethyl acetate and water stirring under the solution room temperature, again ethyl acetate layer is concentrated into dried, residue is dissolved in the small amount of methanol, carries out column chromatography with Sephadex LH-20, uses methanol-eluted fractions, the stream part that will contain desired product is concentrated into dried, the title compound shown in the 4.6mg formula (50).
FAB-MS(m/z)：566[M]
+
1H-NMR(400Hz，DMSO-d
6)，δ(ppm)：11.9
(1H，s)，10.8(1H，brs)，9.07(1H，dd，J＝5.
8，8.8Hz)，9.01(1H，dd，J＝5.0)，8.8Hz)，8.
45(1H，s)，7.93(1H，brd，J＝8.8Hz)，7.44
(1H，brd，J＝8.8Hz)，7.27(2H，m)，6.28(1H，
d，J＝8.8Hz)，6.20(1H，brs)，5.42(1H，
brs)，5.13(1H，brd，J＝5.4Hz)，4.96(1H，d，
J＝5.4Hz)，4.09(1H，brd，J＝7.3Hz)，3.94
(2H，m)，3.83(1H，brd，J＝7.3Hz)，3.58(1H，
m)，3.45(1H，m)
Embodiment 49
Compound shown in the formula (51)
Wherein Bn represents benzyl.
100g 6-benzyloxymethyl-11; 11-benzyloxy-12,13-dihydro-5H-indoles be (2,3-a) pyrrolo-(3 also; 4-c) carbazole-5; 7 (6H)-diketone, 1,4g silver suboxide and 0.7g 4A molecular sieve are suspended in the 40ml dry-out benzene; with suspension reflux 20 minutes; then in 10 minutes toward wherein dripping 1-bromo-2,3, the 5-three-O-ethanoyl-solution of D-ribose in the 10ml dry-out benzene.Again mixture heating up was refluxed 3 hours, use the diatomite filtration insolubles.
Filtrate is concentrated into dried, and residue is dissolved in the 100ml ethyl acetate, uses 0.2N hydrochloric acid continuously, and water and saturated salt are washed this solution, use anhydrous sodium sulfate drying, are concentrated into dried.Residue is dissolved in the chloroform, carry out column chromatography (2.5 * 20cm) with Sephadex LH-20, use the chloroform wash-out, the stream part that contains desired product be concentrated in, residue carries out chromatography (2.5 * 25cm) with silica gel, with toluene-eluent ethyl acetate (3: 1), the stream part that contains desired product is concentrated into dried, and residue advances-goes on foot with preparation algal layer chromatography purify (toluene-ethyl acetate=5: 1, (Rf=0.6)), get 20.8mg 6-benzyloxymethyl-1,11-benzyloxy-12,13-dihydro-(β-D-ribofuranosyl)-5H-indoles is (2,3-a) pyrrolo-(3 also, 4-c) carbazole-5,7 (6H)-diketone.
20.8mg above-claimed cpd is dissolved in the single hydrazine hydrate of 2ml, stirring at room solution 2 hours, mix with the 30ml ethyl acetate, use 0.2N hydrochloric acid continuously, water and saturated salt washing mixture is concentrated into driedly, and residue is dissolved in the methyl alcohol, with Sephadex LH-20 carry out column chromatography (1.0 * 15cm), use methanol-eluted fractions.The stream part that will contain desired product is concentrated into dried, and residual residue is purified (chloroform-methanol=10: 1 (Rf=0.5)) with the preparation thin layer chromatography again, protects the title compound shown in the 2.9mg formula (51).
Rf value: 0.5 (silica gel 60F
254(Kiesel gel 60F
254, Merck Co.); Developping agent, chloroform: methyl alcohol=10: 1)
FAB-MS(m/z)：684[M]
+
1H-NMR(300MHz，DMSO-d
5)，δ(ppm)：10.45
(1H，s)，8.90(1H，d，J＝0.75Hz)，8.68(1H，
d，J＝0.75Hz)，7.18(2H，d，J＝0.75Hz)，7.11
(2H，d，J＝0.75Hz)，7.20-7.50(11H，m)，5.
35-5.45(5H，m)，5.17(1H，d，J＝0.38Hz)，5.
10(1H，d，J＝0.45Hz)，4.98(2H，s)，3.90-4.
00(2H，m)，3.60-3.70(2H，m)
Embodiment 50
Compound shown in the formula (52)
33.0mg embodiment A gained compound is dissolved in 3ml N, in the dinethylformamide, add 8.4ml glycoloyl hydrazine, in 80 ℃ mixture was stirred 2 days, be concentrated into dried, residue is dissolved in the small amount of methanol, (1.5 * 25cm) use methanol-eluted fractions to carry out chromatography with Sephadex LH-20, the stream part that will contain desired product is concentrated into dried, resistates is dissolved in the 30ml ethyl acetate, wash solution with water, with the anhydrous sodium sulfate drying ethyl acetate layer and be concentrated into driedly, residue is dissolved in the small amount of methanol, carry out column chromatography (1.5 * 15cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, the title compound shown in the 29.0mg formula (52).
FAB-MS(m/z)：593[M+H]
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)：11.00
(1H，s)，10.55(1H，s)，10.41(1H，s)，10.02
(1H，s)，8.63(1H，d，J＝7.8Hz)，8.47(1H，d，
J＝7.8Hz)，7.20(2H，t，J＝7.8Hz)，7.04(3H，
m)，5.88(1H，t，J＝7.0?H?z)，5.41(1H，d，J＝6.
2Hz)，5.35(1H，br)，5.20(1H，d，J＝6.2Hz)，
4.90(1H，d，J＝6.2Hz)，4.16(2H，d，J＝5.
7Hz)，4.03(2H，m)，3.74(1H，m)，3.59-3.68
(2H，m)，3.39(1H，m)
Embodiment 51
Compound shown in the formula (53)
35.0mg the compound that embodiment A obtains is dissolved in 1.0ml N, in the dinethylformamide, adds 35.0mg oxalic acid ethyl hydrazine (ethyl-hydiazine oxalate) and 0.5ml saturated sodium bicarbonate aqueous solution.Mixture stirred 1 day in 80 ℃, was concentrated into driedly, and residue is dissolved in the small amount of methanol, carry out column chromatography (1.5 * 15cm) with Sephadex LH-20, use methanol-eluted fractions, the stream part that contains desired product is concentrated into dried, obtains the title compound shown in the 20.8mg formula (53).
Rf value: 0.5 (silica gel 60F
254(Kiesel gel 60F
254, MerckCo.); Developping agent, chloroform: methyl alcohol: tetrahydrofuran (THF)=2: 1: 1)
FAB-MS(m/z)：563[M+H]
+
1H-NMR(300MHz，DMSO-d
6)，δ(ppm)：10.90
(1H，s)，10.35(1H，s)，9.96(1H，s)，8.72
(1H，d，J＝7.9Hz)，8.54(1H，d，J＝7.9Hz)，7.
17(2H，t，J＝7.9Hz)，7.03(3H，m)，5.72(1H，
t，J＝4.8Hz)，5.41(1H，d，J＝6.3Hz)，5.35
(1H，t，J＝4.0Hz)，5.21(1H，d，J＝4.0Hz)，4.
87(1H，d，J＝6.3Hz)，3.96-4.09(2H，m)，3.
73-3.77(1H，m)，3.58-3.67(2H，m)，3.37-
3.45(1H，m)，3.07(2H，m)，1.09(3H，t，J＝7.
1Hz)
Embodiment 52
The 600g poly(oxyethylene glycol) 400 that the compound of 50g embodiment 5 is dissolved in the Japanese Pharmacopoeia is dissolved in the solution of 400g distilled water for injection formation.Strainer with 0.2 μ m removes by filter bacterium, according to a conventional method, 5ml filtrate is packed in the bottle of washing and sterilizing, the bottle top plug is added a cover, whenever and in contain the injection liquid of the compound of 250mg embodiment 5.Give with the intravenous drip method: the above-mentioned injection liquid of 5-10ml (compound of 250-500mg embodiment 5) is made a drops with 500ml preserved material (as 5% glucose) dilution.
Claims (6)
1. compound and the pharmacy acceptable salt thereof shown in the formula [I], formula [I] is:
Wherein:
R
1And R
2Represent hydrogen atom separately, C
1-6Alkyl, C
1-6Alkenyl, C
1-6Alkynyl has the aryl of 6-12 carbon atom, aralkyl or contain 1 to 4 and be selected from nitrogen, oxygen, heteroatomic 5 yuan or 6 yuan of heterocyclic radical (C of sulphur atom
1-6Alkyl, C
1-6Alkenyl, C
1-6Alkynyl has the aryl of 6-12 carbon atom, and aralkyl and heterocyclic radical each can have 1 to 4 to be selected from following substituting group: carboxyl, formamyl, sulfo group, amino, cyano group, list-C
1-6Alkylamino, two-C
1-6Alkylamino, hydroxyl and halogen atom), or formula-Y-R
3Group, and wherein Y represents carbonyl, thiocarbonyl group or alkylsulfonyl, R
3The expression hydrogen atom, C
1-6Alkyl, cycloalkyl, cycloalkylalkyl has the aryl of 6-12 carbon atom, aralkyl, C
1-6The alkoxyl group diazanyl, amino, fragrant amino formamyl, or contain 1 to 4 and be selected from nitrogen, the heterocyclic radical (C of heteroatomic 5 yuan or 6 yuan of oxygen and sulphur
1-6Alkyl; cycloalkyl; cycloalkylalkyl has the aryl of 6-12 carbon atom, aralkyl and contain 1 to 4 and be selected from nitrogen; heteroatomic 5 yuan or 6 yuan of heterocyclic radicals of oxygen and sulphur each can have 1 to 4 to be selected from following substituting group: halogen atom; the hydroxyl of optionally being protected, amino, carboxyl; formamyl, cyano group and C
1-6Carbalkoxy, but and C amino and that each freedom of formamyl is optionally replaced
1-6The alkyl list-or two-replacement, wherein C
1-6The substituting group of alkyl is selected from following groups: halogen atom, hydroxyl, amino, carboxyl, formamyl and C
1-6Carbalkoxy); Or
R
1And R
2Combine expression C
1-6Alkylidene group (C
1-6Alkylidene group can have 1 to 4 to be selected from following substituting group: amino, list-C
1-6Alkylamino, two-C
1-6Alkylamino, hydroxyl, carboxyl and alkylsulfonyl); Or
R
1And R
2The nitrogen-atoms that is connected with them combines 5 yuan or 6 yuan the heterocyclic radical that forms nitrogen atom, and this heterocyclic radical also can further contain 1 to 3 and be selected from nitrogen, and oxygen and sulphur atom (can have the C that is optionally replaced on the heterocycle
1-6Alkyl, this C
1-6The substituting group of alkyl is selected from: amino, hydroxyl, carboxyl and sulfo group),
G represents pentose base or hexose-based,
X
1And X
2Represent hydrogen atom separately, halogen atom, amino, list-C
1-6Alkylamino, two-C
1-6Alkylamino, hydroxyl, C
1-6Alkoxyl group, aralkoxy, carboxyl, this C
1-6Carbalkoxy or C
1-6Alkyl.
2. the described compound of claim 1, this compound are the compounds of formula [Ia] representative, and formula [Ia] is:
Wherein
R
11And R
21Represent hydrogen atom separately, C
1-6Alkyl, C
2-6Alkenyl has the aryl of 6 to 12 carbon atoms, C
6-12Aryl C
1-6Alkyl, pyrryl ， oxazolyl ， isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl ， oxazolinyl ， oxazolidinyl, imidazolinyl, imidazolidyl, pyrrolidyl, piperazinyl, thiazinyl, thiazolidyl (C
1-6Alkyl, C
2-6Alkenyl has the aryl of 6 to 12 carbon atoms, C
6-12Aryl C
1-6Alkyl and heterocyclic radical can have 1 to 5 and be selected from following substituting group carboxyl, formamyl, cyano group and hydroxyl), or formula-Y-R
31Base, and wherein Y represents carbonyl, thiocarbonyl group or alkylsulfonyl, R
31The expression hydrogen atom, C
1-6Alkyl, C
6-12Aryl (C
1-6Alkyl and aryl can have 1 to 4 to be selected from following substituting group: halogen atom, Bao Hu hydroxyl optionally, amino and carboxyl), amino, diazanyl, C
6-12Arylamino, C
1-6Alkoxyl group, formamyl, pyrryl ， oxazolyl ， isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl ， oxazolinyl ， oxazolidinyl, imidazolinyl, imidazolidyl, pyrrolidyl, piperazinyl, thiazinyl or thiazolidyl; Or
R
11And R
21Expression optionally has the alkylidene group of carboxyl altogether; Or
R
11And R
21Combine with the nitrogen-atoms that is connected with them and can form pyrrolidyl, imidazolidyl, imidazolinyl, piperidino-(1-position only), piperazinyl (can have the C that is optionally got base by hydroxyl on these heterocycles
1-6Alkyl),
G
1Expression following formula group
Or
R wherein
7Expression hydrogen atom or C
1-6Alkyl, R
8Expression hydroxyl or amino, and
X
11And X
21Be connected in respectively the 1-of indoles and pyrrolocarbazole ring or 2-position and 10 or the 11-position on, represent halogen atom separately, hydroxyl, C
1-6Alkoxyl group or C
6-12Aryl C
1-6Alkoxyl group.
3. the described compound of claim 1, this compound are the compounds of formula [Ib] representative, and formula [Ib] is:
Wherein
R
12Expression hydrogen atom or C
1-6Alkyl,
R
22The expression hydrogen atom, C
1-6Alkyl (C
1-6Alkyl can have 1 to 5 to be selected from following substituting group: carboxyl, formamyl, hydroxyl and cyano group), C
6-12Aryl, C
6-12Virtue C
1-6Alkyl (aryl and aralkyl can have 1 to 4 substituting group that is selected from hydroxyl and carboxyl), pyridyl, imidazolyl, imidazolinyl, thiazolyl, pyrrolidyl, piperazinyl, or formula-Y-R
32Group, and Y represents carbonyl, thiocarbonyl group or alkylsulfonyl, when Y is carbonyl or thiocarbonyl group, R
32The expression hydrogen atom, C
1-6Alkyl, C
6-12Aryl (C
1-6Alkyl or C
6-12Aryl can have 1 to 4 to be selected from following substituting group: halogen atom, protected hydroxyl optionally, amino and carboxyl), amino, diazanyl, C
6-12Arylamino, C
1-6Alkoxyl group, formamyl, pyridyl, pyrimidyl, imidazolinyl, or pyrrolidyl, when Y is an alkylsulfonyl, R
32Expression C
1-6Alkyl or 6-12 aryl; Or
R
12And R
22Expression has the alkylidene group of carboxyl altogether; Or
R
12And R
22Combine with the nitrogen-atoms that is connected with them and can form pyrrolidyl, piperidino-(1-position only) or piperazinyl (can have the C that is optionally replaced by hydroxyl on these heterocycles
1-6Alkyl),
G
1, X
11And X
21Identical with its definition in claim 2.
4. right is for asking 1 described compound, and this compound is the compound of formula (5) representative, and formula (5) is:
5. with the compound and the derivative thereof of following formula [III] representative, general formula [III] is:
X wherein
1, X
2Identical with G with its definition in claim 1.
6. antitumor medicine composition comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the thinner of the described formula of claim 1 [I] representative of significant quantity, and formula [I] is:
R wherein
1, R
2, X
1, X
2Identical with G with its definition in claim 1.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP69269/92 | 1992-02-18 | ||
| JP6926992 | 1992-02-18 | ||
| JP25730692 | 1992-09-01 | ||
| JP257306/92 | 1992-09-01 |
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| Publication Number | Publication Date |
|---|---|
| CN1075482A CN1075482A (en) | 1993-08-25 |
| CN1035878C true CN1035878C (en) | 1997-09-17 |
Family
ID=26410463
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100326A Expired - Fee Related CN1035878C (en) | 1992-02-18 | 1993-01-02 | Indolopyrrolocarbazole derivatives |
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| Country | Link |
|---|---|
| CN (1) | CN1035878C (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991018003A1 (en) * | 1990-05-11 | 1991-11-28 | Banyu Pharmaceutical Co., Ltd. | Antitumor be-13793c derivative |
| JPH09120277A (en) * | 1995-03-21 | 1997-05-06 | Sun Microsyst Inc | Device and method for synchronization of independent frame buffer |
-
1993
- 1993-01-02 CN CN93100326A patent/CN1035878C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991018003A1 (en) * | 1990-05-11 | 1991-11-28 | Banyu Pharmaceutical Co., Ltd. | Antitumor be-13793c derivative |
| JPH09120277A (en) * | 1995-03-21 | 1997-05-06 | Sun Microsyst Inc | Device and method for synchronization of independent frame buffer |
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| Publication number | Publication date |
|---|---|
| CN1075482A (en) | 1993-08-25 |
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